1. The World Life Lives In (1,107)

It's easy to underestimate how incredible a single cell in your body really is.

A typical human cell is vanishingly small, yet contains an enormous number of molecules packed into a tiny space.

The molecules aren't static. They move constantly and randomly, jostling and colliding, driven by thermal energy. Nobody is running the show. There are only molecules colliding and interacting with each other through local, physical forces.

From this activity, life emerges.

Cells build complex structures. They carry out coordinated sequences of actions. They respond to changes in their environment. They reproduce. All of this happens reliably, even though it depends on innumerable blind interactions.

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

To understand how this occurs, we need to look closely at how cells function. But to do that, we first need a clearer picture of what a cell actually looks like.

Picturing the cell

We all have mental pictures of cells--organelles like mitochondria, the DNA double helix and the like--from high school or college. Biology is full of neat and tidy diagrams. They’re indispensable. There are many in this book.

But while they're necessary, diagrams in molecular biology can also mislead.

Every diagram or figure--every representation of any real thing--simplifies the world to emphasize the aspect being highlighted. Salient features are distilled out of a larger reality that can get overlooked.

In this book, we want to get our heads around not only the details of genome replication but also the larger picture of the cell and of life itself. We want to gain a more complete mental picture than can be depicted soley with diagrams of the details.

That reality is far less orderly than the diagrams alone suggest.

A chaotic place

A human cell is so small that about 1,000 could fit on the period at the end of this sentence. Yet there are about 1-3 billion protein molecules in every cell.

We’ll be spending a lot of time talking about proteins in this book. Inspite of the fact that there are billions in every cell, they’re real. They have mass and take up space. And they do most of the work in the cell.

These proteins--and everything else in the cell--are surrounded by water molecules that have kinetic energy, or energy of motion. They jostle and jiggle constantly. As they do, they ram into proteins and other molecules causing them to move around the cell very rapidly.

To give you a sense of just how rapidly, in one second, one protein inside a human cell will collide with about a million other non-water molecules, many of them other proteins. That’s how fast they’re moving and how crowded the space is.

This constant motion turns out to be essential to life.

Speed matters

Proteins are like little machines inside cells.

For now, think of a protein as roughly globular, or spherical, with a specific location or site on its surface that accepts the attachment of another protein or smaller molecule--like a key in a lock.

That second protein or smaller molecule lodges in the first protein's site in order to be chemically altered in some way. But--and this is the critical point--for that to occur, the first protein must collide with the other protein or other small molecule in exactly the right orientation.

It seems like it would be extremely rare for this to occur--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 two orientations.

But with billions of proteins moving so rapidly and crashing into each other a million times per second, the chance that the right two molecules will collide in the correct orientations increases enormously.

Crowding and high-speed motion ensure that nearly every possible collision and interaction will occur rapidly and repeatedly. Most collisions will be unproductive. But productive encounters become inevitable given the number of attempts.

The lesson is that life requires molecules darting around randomly at extremely high speeds; that is, high relative to the size of a cell. Biological precision doesn’t arise in spite of molecular motion. It arises because of it.

Intuition breaks down

The conception of a cell as random yet precise at the same time 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.

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 a particular binding site is occupied or not.

The more we appreciate how life works, the harder it becomes to reconcile its precision and reliability with its blindness.

Genome replication: the stress test

The replication of the human genome, which occurs every time a cell divides, is arguably the most exacting process that cells perform.

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.

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

Thousands of points of replication on the genome operate in parallel. Dozens of different proteins must be present at each site of replication 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.

Errors are rare but, given the size of the genome, inevitable.

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 integrates almost every major concept in molecular biology. If order without a planner occurs in the cell, it occurs here.

What this book will do

Understanding how this works will require building up the pieces step by step.

We’ll begin with the basic components of the cell--what they are and what they do--before turning to one of the most demanding processes in biology: the replication of the human genome prior to cell division.

The goal is not to make this or any other cellular process feel less strange, but to make the strangeness unmistakable.

By the time genome replication is fully described, the most surprising aspect will be that it can exist at all--that chemistry, left to itself, can come to life.