1. The World Life Lives In

I've always been amazed at life at the cellular level. Inside your 50 trillion or so cells, untold numbers of molecular machines are performing complex tasks with incredible precision. Yet nobody is running the show. Everything that takes place there--in fact, life itself--arises seemingly spontaneously from inanimate matter randomly crashing around. How can molecular precision arise from apparent molecular randomness?

​In this book, I try to paint a clear picture of the cellular world that underscores this seeming contradiction. I'll present the cell's activities at a deeper level than is typically presented to a general audience. The content of the latter part of this book will be at or above the level of a graduate school course. My challenge is to make it accessible.

To go deep, though, we can't go too wide. So, after covering some foundational molecular biology, our focus will be on just one of the cell's activities: the process by which it copies, or replicates, its genome prior to each cell division. It's a massive task, and the steps the cell goes through to accomplish it are mind boggling. Understanding genome replication will give you a very good sense of what life looks like and how life "works."

Picturing the cell

We all have mental picture of a cells, cell organelles like mitochondria, the DNA double helix and the like. We were undoubtedly subjected to them in high school or college biology courses. In fact, biology is full of neat and tidy diagrams and drawings. They’re indispensable. There are many in this book.

But while they are necessary, diagrams in biology, especially molecular biology, can also mislead. Every diagram or figure—every representation of a 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’re trying to get our heads around not only the details of genome replication but also the Gestalt—the organized whole—of the cell and of life itself. To do that, we’ll need a more accurate mental picture of the overall cell than can be depicted in diagrams of the details.

A chaotic place

Consider the cell. If you could look at it at the molecular scale, you’d see that it is an extremely crowded, chaotic place. Proteins, the workhorse molecules in cells, are beyond numerous. A single 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 proteins in that one cell! We’ll be spending a lot of time talking about proteins. But they’re real. They have mass and take up space.

This population of proteins inside the typical human cell includes about 10,000-20,000 different types. So, doing some quick math, on average there might be 150,000 or so of a given type of protein in a human cell. But the range is wide. Some proteins are present in millions of copies and others in tens or hundreds.

These proteins and other large molecules 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 larger molecules, causing them to move around the cell constantly.

These billions of proteins are made to move extremely rapidly. In one second, a single protein inside a human cell will collide with about one million other large (non-water) molecules, many of them other proteins. That’s how fast they’re moving and how crowded the space is. If we include collisions with water molecules in addition to collisions with larger molecules, a given protein’s collisions per second would be in the billions!

The subcellular world can be hard to get one’s head around. I’ll speak to that in a moment. But first, I want to explain why it matters that there are so many proteins moving so rapidly and crashing into each other so frequently.

Why this matters

Proteins are like little machines inside cells. For now, just think of a functional protein (a protein that does a job inside the cell as opposed to a protein that plays a structural role) as roughly spherical with a specific site somewhere near its surface that accepts the attachment of another protein or smaller molecule—like a key in a lock.

That other protein or smaller molecule lodges in the site typically: (1) to attach itself to the first protein, often to be chemically altered in a specific way, (2) to attach a specific chemical group to the first protein to some effect, or (3) to remove a specific chemical group from the first protein to some effect.

The key point is this. For these actions to occur, though, the first protein must collide and interact with the other protein or smaller molecule at exactly the right position on that first protein. In fact, both colliders must be in exactly the right orientation when they collide for the action to occur.

It might seem that it would be very rare for a specific kind of protein A to collide into a specific kind of protein B (or other specific 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.

Who knew that molecular biology was kind of a statistical numbers game? A quick thought experiment. If molecular motion were 1,000 times slower, what would happen? Collisions would be much rarer and the “right collisions” even rarer. Proteins would sit idle. Life would come to a halt. Life requires molecules darting around at extremely high speeds.

Thus, biological precision doesn’t arise in spite of molecular motion. It arises because of it! Crowding and high-speed motion ensure that every possible collision and interaction will occur rapidly and repeatedly. The great majority of collisions will be unproductive. The molecules will just bounce off each other. But productive encounters become inevitable given the number of attempts.

Why intuition breaks down

The picture of the cell I’ve painted is deeply unintuitive to the human mind and the shift to the cellular and molecular world can be disorienting. Human intuition evolved to navigate a world of visible, human-sized objects generally moving at much slower speeds. Cells and molecular systems operate under neither of these conditions.

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

Think about it. 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 knows is limited and immediate. It knows if a particular binding site is occupied or not.

As I hope you experience reading this book, the more we see how life works, the harder it becomes to reconcile its precision and reliability with its blindness. This tension is not something this book will try to resolve. In fact, it’s something I still struggle with after a lifetime in the field of molecular biology.

Genome replication: the stress test

The replication of the human genome, which occurs each time a cell divides, is arguably the most exacting process in cells. In human cells, specifically, over six billion bases must be copied (two three-billion base genomes… one each from mom and dad). This must be done quickly (in about eight hours), accurately (the copied six billion bases will end up having just a handful of errors) and exactly once per cell division (copying a region more than once would create a mess).

Thousands of points of replication on the genome (replication forks) operate in parallel. Dozens of different proteins must be present at each fork 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. Genome replication is industrial-scale production and quality control involving hundreds of molecules that lack awareness, intention, or foresight.

This is why DNA replication serves as the central case study in this book. It integrates almost every major concept in molecular biology: specificity, coordination, error detection, error repair, redundant pathways and precise timing. If order without a planner occurs in the cell, it occurs here.

What this book will do

The chapters that follow will take you step-by-step first through some basic molecular biology principles and then to a detailed account of how human cells replicate their genomes. There will be no appeals to mystery and no suggestion that life’s complexity requires anything more than ordinary matter obeying ordinary physical and chemical laws.

The goal of this book isn’t to make these processes feel less strange. It’s to make the strangeness crystal clear. By the time genome replication is fully described, the most unbelievable aspect of the process will be that it can possibly exist at all… that chemistry, left entirely to itself, can come to life.

Let’s begin our journey!