1. The Cellular World (1,144;7/2)

A single human cell is easy to overlook. It’s so small that roughly 1,000 could fit on the period at the end of this sentence. Yet, inside that space exists a world of astonishing activity and complexity.

That cell contains billions of protein molecules along with DNA, RNA, sugars, fats, countless smaller compounds and ions. These molecules aren't static. They move randomly at very high speeds--that is, very high relative to the size of the cell.  

They move because they are constantly bombarded by surrounding water molecules that are in rapid motion. The water molecules continually collide with proteins and other molecules, causing them, in turn, to move around the cell and collide with each other.

Every second a given protein in a human cell will collide with billions of water molecules and millions of other molecules. Seen through this lens, the cell is anything but precise and orderly. It’s extremely crowded, restless and random.

And yet, from this restless, random activity, astonishingly complex life processes emerge. The molecules within cells carry out coordinated sequences of actions. They build intricate structures. They manipulate other molecules. They transport materials from one location to another. They respond to changes in the environment. And at the cell level, there is growth, division, damage repair, and reproduction. All of this happens reliably.

How can precision arise from molecular randomness? How can a cell's components be completely unsupervised, yet produce processes that are mechanistically intricate and outcomes that are precise and consistent?

To answer these questions, we need a preliminary idea of how one of the key types of cellular components, proteins, function.

Motion and crowding

We’ll be introduced to many different proteins in this book. In a few chapters I'll describe proteins as little machines inside cells. They do almost all the work, and each kind has a specific job. But the general way they accomplish their diverse tasks follows a common pattern.

For now, imagine a protein as a small object with a surface or surfaces that can selectively interact with other molecules. When the right molecules encounter one another, they can bind and trigger chemical or structural changes. Often these chemical or structural changes made to the second molecule are caused by a shape change--or, in science-speak, a conformation change--in the first protein.

But--and this is the critical point--for this to occur, the first protein must collide with the other protein or small molecule in exactly the right two orientations. 

It seems like it would be extremely rare for this to occur--that is, for a specific kind of protein A to collide into a specific kind of protein B (or other smaller molecule B) in exactly the right orientations. But with billions of proteins moving so rapidly and crashing into other molecules a million times per second, the chance that the right two molecules will collide in the the right orientations increases enormously.

High speed motion and crowding ensure that an enormous range of collision and interaction occur rapidly and repeatedly. Most collisions will be unproductive. But productive encounters become inevitable given the number of attempts. Biological precision doesn’t arise in spite of molecular motion and crowding. It arises because of it.

Intuition breaks down

The conception of a cell as random yet precise is deeply unintuitive and the shift to the cellular and molecular world can be disorienting. Human intuition evolved to navigate a world of visible, human-sized objects moving at relatively slow speeds. Cells and molecular systems operate under neither of these conditions.

Human intuition associates organization and coordination with centralized control and planning. Biology achieves incredible organization and coordination without either centralized control or planning.

No protein oversees the cell’s activities. For a given protein at the local level, there is no long-range awareness. A protein doesn't "know" what’s happening in other parts of the cell. What it is "aware of" is limited and immediate--mainly, if its binding site is occupied or not. And yet these blind interactions collectively generate stable, reliable behavior.

A traffic jam forms without anyone designing it. An ant colony builds pathways to food sources and livable structures without a master architect. In a similar way, the cell achieves remarkable coordination through countless continuously occurring molecular interactions.

This is one of the central themes of the book: order can emerge from immense numbers of local interactions, even if no component understands the larger system.

Genome replication: the stress test

Few processes reveal cellular precision in a chaotic environment more dramatically than the replication of a cell's genome. Every day in a human body, billions of cells undergo division, a process requiring near-perfect duplication of more than six billion base pairs of DNA. It's arguably the most exacting process cells perform. 

Genome replication is not just a mechanical task of copying data; it's a highly orchestrated process performed with a degree of rigor that allows for less than one error every billion nucleotides. And this process must unfold quickly--in about eight hours.

Thousands of replication sites on the genome will operate in parallel. Dozens of different proteins must be present at each site and interact in precise ways. The entire process unfolds in a crowded, noisy environment while the DNA itself is constantly being degraded by heat, chemicals and radiation.

The rate of replication errors is very low but, given the enormous size of the genome, they are inevitable and numerous. What’s most remarkable isn’t the low rate of errors, but the fact that the ones that get through are detected, corrected or tolerated without derailing the process. 

DNA replication will serve as our window into how life itself works, helping us build a concrete picture of how living processes emerge from nonliving parts.

What this book will do

To get our heads around human genome replication, though, we first need to understand the world in which it occurs. We need to make an investment to demystify the cellular context in which replication takes place.

Thus, the first half of this book will focus on the basic components and functioning of human cells--what they are and what they do--before turning to the process of human genome replication in the second half. A close look at genome replication will reveal the diverse and complex types of molecular interactions that must occur for cellular processes to take place and for life to happen.

My expectation with this book is that the more you learn about genome replication and repair, the harder it will become to believe that the process emerges from molecules that possess no awareness, plan, or understanding of the larger task. The ultimate goal of this book is not to make genome replication or other cellular processes feel less strange, but to make the strangeness of life at the molecular level clear and unmistakable.

To do that, we first must step back and ask a basic question: What's a cell?