development – Thinking with Nate

Building Bodies

(The image for this post is a human embryo after six days of development: a blastula. The structure needed to construct a body is just starting to take form. Before this point, it’s mostly just a lump of undifferentiated cells. Image credit: Jenny Nichols)

Humans live in the macroscopic world. We’re used to interacting with other people and animals that are about the same size as us. Of course, everything we see as an “individual” is actually made up of unimaginably vast numbers of cells and molecules in constant churning motion, but to us they just look like solid, physical objects. This is normal to us, but it’s a totally alien experience to our most primitive ancestors. We are descended from individual cells that lived fully autonomous lives in a microscopic world. It’s truly extraordinary and weird to think that they would band together by the trillions to form human bodies, and yet that’s what they do. How did that come to be?

Our ancient ancestors were protists, single cells with complex lives. Each one had to find food, shelter, and resources. Just as we do, they continuously decided how to live, trying to survive and thrive in a chaotic world, and to set their children up for success. Sometimes they lived in communities and ecosystems, building networks of mutually supportive relationships. They’d form vast colonies of closely related cells, generally working together, communicating, maybe even specializing and subdividing tasks. And yet, each cell was still responsible for its own well-being. There was no top-down coordination. Each individual decided for themselves what to do. Cooperation would naturally arise when it was useful, and break down again the moment incentives changed.

As we now know, cells can do extraordinary things when they work together on a shared plan. In today’s animals, each cell has an established role to play. Collectively they build complex, macroscopic bodies that observe, think, move, and reshape the world at a vastly larger scale. But try telling that to a single cell! For two billion years, they were honed by evolution to fight tenaciously for their own survival as free-living individuals, and to prioritize their well-being and their offspring. Collectively, the cells of a macroscopic individual may fare better than they would alone, but not all of them. Think of the cells that line your stomach, whose life’s purpose is to get dissolved by acid so that other cells don’t have to. How does evolution convince a cell to do that voluntarily?

More importantly, most animal cells are evolutionary dead-ends. We have specialized sex cells whose only job is to produce children. Every other cell in the body is denied that privilege. Many of those cells still divide occasionally, but all their offspring will die out when the body does. They have no way to influence the next generation of their species. This is a huge contradiction, because those cells evolved for reproduction. For billions of years, the cells who contributed the most to the next generation were favored. Perhaps the most fundamental fact about life is that it proliferates, rapidly filling up every corner of the planet. How do you reverse this core instinctual drive in every living cell?

It’s quite likely that multicellularity evolved and fell apart many times. Discovering this trick is very hard, for the reasons outlined above and more. What’s even harder, though, is holding onto this innovation once it’s found. In order to maintain an animal body, every cell must compromise its well-being for the good of the whole, for a lifetime. If any cell decided to cheat—to live as a rebel among conformists, and selfishly exploit the body environment—it would have a distinct and powerful advantage. It would outperform the others, undermine their hard work, proliferate much faster, maybe even start a whole new successful family line as single cells, feasting on the remnants of the would-be body. Mutations that broke multicellularity must have been common!

Yet, today we live in a multicellular world. How did we make that work? There’s an interesting theory to explain this, and it explains something else strange, too: every single multicellular organism has sex. Some reproduce asexually, too, but the mechanism of sexual reproduction is universal. This is not at all the case for single cells. They exchange genetic material with other cells, but they don’t depend on others to reproduce. They do that entirely on their own, using whatever genes they have at the time. So, perhaps sex and multicellularity are linked? Perhaps sex came first, and is part of what made multicellularity possible? There are a few good reasons to think this, but for me the most compelling is that sexual reproduction creates mothers, and puts them in control.

Generally speaking, the process of building an animal body is decentralized. There is a sort of top-down coordination, using patterns of hormones and bio-electricity to shape a coherent whole, but this has to be generated by the cells themselves. Every cell autonomously figures out where to be and what role to play, via coordination with its neighbors—but not at first! At the very beginning of the process, the embryo’s genes are switched off and the mother’s genes direct the first stages of growth. In an egg or a womb, the mother also has full control over the environment in which development happens, which further shapes the process even once the embryo takes over. This gives Mom the power to set things up just right such that multicellularity is the only viable outcome.

The single cells of an early embryo aren’t a body yet. They default to the independent lifestyle they had for two billion years before the advent of multicellularity. The cells have to work together to build an organism with unified awareness and agency, but that means at first there isn’t one. There’s nobody to coordinate the cells, and no “greater good” to serve. Why should they work together? That’s where the mother comes in. She takes full control and forces the cells into the right starting configuration. She shapes the growing embryo and assigns roles to each cell by tweaking their gene expression. The child cells only get to take over once the general layout of the embryo is established, and the growth process is already underway. Once an individual emerges from the collective behavior of those cells, it can carry on the rest of the work of building a body.

From that point on, there’s very little temptation to cheat. The clockwork of the body has been set into motion. Each cell’s needs are provided for, and their freedom is restrained by the bonds they’ve already formed with their neighbors. The reproductive cells have already been isolated, making it impossible for rogue cells to influence the next generation. They could still rebel and do their own thing. That’s what cancer is. But it’s much harder than playing along, and carries serious risks. The immune system actively hunts for rebellious cells, and kills them on sight! It’s also a futile exercise. A cancer may grow and thrive and proliferate for years, but this is self defeating. When the cancer cells undermine the host body, they destroy their own environment and drive themselves to extinction.

Once cells are locked into this multicellular arrangement, something interesting happens to the selective forces that shape their evolution. As always, the reproductive cells carry subtle genetic differences from their parent, tiny mutations that serve as evolutionary experiments. Changes in an egg cell’s genes affect the behavior of every cell that follows, and thus the body and behavior of the child as a whole. But a new selective filter has been established. Only variations that are beneficial to both the cells and the individual are allowed through. Mutations that damage either level of the system produce unfit individuals who often won’t even develop to maturity. This creates a pressure for cells to become more cooperative building blocks, and for bodies to become more supportive homes for cells.

The takeaway here is that each living cell is a creative, intelligent, and autonomous survival machine. That makes multicellularity a tricky balancing act that’s hard to discover, and even harder to maintain. It seems likely that sexual reproduction and motherhood were essential ingredients to make this possible. In a sense, multicellularity isn’t passed on genetically, it’s passed on physically; each multicellular organism has to assemble the next generation from individual cells before that child can carry on building itself. The cells don’t know how to do it on their own, and they don’t care to. Yet, once a mother forces them into the shape of a growing embryo, it’s in each cell’s best interest to play along. For about 1.5 billion years, evolution has worked hard to maintain this tenuous arrangement by aligning incentives between cells and bodies. Both systems coevolve to complement each other, to ensure the multicellular compromise is the wise choice going forward, for everyone involved.

This is a speculative story, but well supported by evidence. It’s largely inspired by The Evolution of Individuality by Leo Buss, a very technical book about cellular and developmental biology, which goes into vastly more depth and detail than I did here about the complex lives of single cells and the struggle to align incentives across multiple scales. In particular, that book explores the very different ways plants and fungi have overcome the challenges of building macroscopic bodies. It’s a fantastic reminder that what animals do is not “normal,” it’s just what we’re used to. We’re actually quite strange and exceptional, as life goes. Most living things are single cells, and even when it comes to bodies, our way of doing it is just one of many. It’s a brilliant and eye-opening book, but a challenging read, so I wanted to write a more accessible summary, to share these ideas more broadly.

Universal Automata

A Cell’s Eye View of Evolution, Part 1

(This month’s image is a photo I took of the full-scale model of Babbage’s Difference Engine at the Mountain View Computer History Museum. This is one of the first examples of a programmable digital computer. It’s a completely mechanical device, operated by hand crank.)

This is part one of a three-part series. For an overview, check out the introduction.

In the traditional story of evolution, each organism lives a single lifestyle, and the forces of nature select which ones are fit enough to reproduce. From that perspective, evolution is something that happens to life. But this story fails to explain something very strange and important: cells are not single-purpose machines. Although they only live one lifestyle at a time, they have the capacity to live an infinite variety of lifestyles, depending on their DNA programming. That requires an enormous amount of complexity and effort that doesn’t directly contribute to a life well lived. In fact, being programmable doesn’t help at all in a single lifetime if the program never changes. So why does life work this way?

To make sense of this, let’s look at a parallel example in computer technology. Consider an ATM. It’s a highly specialized kind of machine, but these days if you look under the hood you’ll often find a Windows PC that’s programmed to be an ATM. That seems like an odd choice at first. ATMs do things most PCs don’t (like dispensing cash), and Windows supports things that you don’t want in an ATM (like running random programs off the internet). You could make a better, safer, more efficient ATM if you designed a custom machine for that purpose, but nobody does that, because it’s harder. Digital computers are so versatile and easy to reprogram that they show up everywhere. As they get used in new applications, their range of capabilities expands, enabling new use cases and further innovation.

Cells are very similar. Being programmable doesn’t help with any one lifestyle, but it makes it possible to explore new lifestyles relatively quickly and easily. Each individual operates in a complex, roundabout way that only uses a fraction of the cell’s potential. That seems like a bad thing, but the adaptability makes it worthwhile. The world is in constant flux, especially once organisms started actively changing things and competing with one another. Very few evolved lifestyles withstand the test of time. For this reason, nature doesn’t just select “the best lifestyles” for life. Life invested in a general purpose platform to make the search for new lifestyles more efficient.

Let’s take a closer look at how the platform works. A cell can be thought of as a kind of microscopic robot. The “programming” for that robot is stored in DNA, which is surrounded by a complex mechanism that reads that data and uses it to produce the form and behavior of the organism. Each cell has a very limited capacity for intelligence, but they’re very good at working together. Like a sort of “autonomous smart matter,” they collaborate by the trillions, which is how every form of intelligence on this planet is made. There’s no reason to think there’s an upper limit to what can be built in this way.

What makes this possible is the protein-synthesis engine at the core of every cell. The nucleus of a cell is a bit like the brain of a human, in that it’s a specialized sort of computer that’s “in control” of the cell. It’s surrounded by the cell’s body, which serves as the interface between the program in its nucleus and the outside world. This is where the similarity ends, though, because the nucleus and the brain are very different kinds of computing devices.

The nucleus works by continuously handling requests, looking up protein recipes, and sending those recipes back out to the cell for construction. A cell can make an astonishing variety of complex molecules this way. These proteins are what make up the cell, its inner workings, and outward behaviors. They serve as building material, messages, tools, or even nano-robots that move about within the cell, manipulating other molecules, and doing useful work all on their own. Sometimes a single protein can serve all of these roles, depending on context. They interact with each other in a vast complex network of activity that keeps the cell alive.

These cellular mechanisms continuously send messages back to the nucleus, reporting on the cell’s health, situation, and needs. The nucleus uses this information to figure out what proteins to make next, adapting the cell’s makeup and behavior to fit the circumstances. For instance, E. coli bacteria normally feed on glucose sugar, but they can eat lactose instead, if that’s what’s available. When that happens, the cell reports to the nucleus that it’s running low on energy and what molecules are around. The nucleus then decides to switch some genes on and off, which instructs the cell to make different enzymes, which results in different cascades of chemical reactions, in order to digest and use the lactose. By reading the DNA differently, the nucleus shifts the whole cell from one lifestyle to another, in response to a changing environment.

Another way to think of the nucleus is as the engine of the cell. The proteins it makes drive all the chemical reactions that keep the cell alive. Ultimately, everything the cell does is about collecting the energy and raw materials to feed that engine and keep it running. This is the cell’s metabolism. When the engine runs faster, the organism becomes more active, moving, “thinking,” and reacting with speed and vigor, but quickly burning through its energy stores. When it runs slowly, the cell becomes sluggish and conserves its energy. If it ever comes to a full stop, the cell dies, or, in special cases, enters suspended animation. In other words: cells live to make proteins, and making proteins is what makes cells alive.

DNA is where the cell keeps all these protein recipes, but the DNA molecule itself is completely inert. It just carries information, like a computer memory card. It can’t do anything by itself, and certainly can’t make a body from scratch. To build an organism, you need a cell to interpret the gene sequence and do the construction. This is why cells always reproduce by splitting in two. The daughter cell is basically just half of the parent cell, full of the same soup of proteins and organelles, in a fully operational state. The only part that’s really “new” are the DNA molecules in the nucleus, freshly copied from the parent(s). Any changes in that DNA program will only manifest when the daughter cell sends a message to the nucleus and gets a different response back than its parent would have seen.

That means that every cell has the crucial responsibility of reading and writing those DNA programs. They contain every useful protein recipe life has discovered, and must be actively maintained over generations or those recipes will be lost. But what does life actually record in the DNA? Geneticists say DNA is made of four amino acid base pairs (A, G, T, C), which are grouped into triplets called “codons” that serve as instructions for protein synthesis. That makes it seem “natural,” as if that were the only way to do it. The truth is, the code is totally arbitrary. Life made it up. By trial and error, life invented a coding scheme. It gave meaning to those molecules and all the ways they can be combined. The programming language of life was invented by life. It wasn’t the beginning, but a tool that cells made to manage their behaviors, learn new ones, and pass knowledge to future generations.

Let’s put that all together. A cell is a programmable micro-robot (in technical jargon, a “universal automaton”), capable of making virtually any protein and living virtually any lifestyle. In a sense, a cell is not just one organism, but potentially an infinite variety of organisms, depending on the programming in its nucleus. But how does the program get written? Life had to do all the work itself, without a programmer in the traditional sense. A cell has no mind with which to analyze its DNA and understand what it means. It cannot imagine the consequences of any changes to its programming, or test them out to make sure they are safe. And yet, somehow life invented a programming language and used it to write countless programs and build the full diversity of organisms we see on Earth.

We’ll delve into the details of how this happened in the next two blog posts. At a high level, though, there are two main parts of the story:

Life is self-made. Each cell is relatively simple and mindless, but working together in huge populations over long stretches of time, they develop their own programming. How they do it is quite different from how a human programmer would, but from a collective perspective, there are also some surprising similarities.
Life influences future generations. Organisms don’t just worry about their own survival, they put an enormous amount of time and energy into influencing the next generation for the better. Science is only beginning to understand this, but it offers the tantalizing possibility that, in some limited sense, life might steer its own evolution.