4. What's Inside a Cell (1,036)

If we were to shrink down by a factor of about 100,000 and enter a human cell, the first thing we'd notice wouldn't be structures. It would be motion.

Not slow, orderly motion--but incessant, chaotic movement.

In the cytosol, the water-based liquid in the cell, countless molecules crowded together would be crashing into each other at high speeds. No guidance system is telling these molecules where to go.

High speeds plus dense crowding guarantee an extraordinarily large number of collisions, which in turn assures that collisions between the right two molecules in the correct orientations will occur frequently enough to sustain life.

Molecule meets molecule

To sharpen our mental picture of molecular motion, I'll quote from David Goodsell's book, The Machinery of Life. He's talking about a bacterial cell, which is thousands of times smaller than a human cell. But the image he paints delivers the right intuition.

"To get an idea how fast this motion is, imagine a typical bacterial cell... and place an enzyme at one end and a sugar molecule at the other. They will bump around and wander through the whole cell, encountering many molecules along the way. On average, though, it will only take about a second for those two molecules to bump into each other at least once.

Goodsell goes on to note that this means that any molecule in a typical bacterial cell will encounter almost every other molecule in a matter of second!

Given these enormous numbers of collisions, productive encounters are not rare--they are inevitable.

What kinds of molecules?

To understand how these interactions actually occur, we need to look at the molecules themselves. They would range from very small to very large with each class of molecule playing a different role in this system of constant interaction.

The smallest and fastest moving molecules would be ions like sodium (Na+), magnesium (Mg2+), calcium (Ca2+), and phosphate (PO43-). Ions create electrical and chemical gradients, stabilize molecular structures, and enable key reactions. They're composed of just one or a handful of atoms.

Next would be metabolites--small molecules like glucose, ATP, amino acids, and the many intermediates of metabolism. Metabolites participate in chemical reactions. They contain tens to about a hundred atoms. They're roughly 10x the size of an ion.

Proteins and smaller RNAs would be next in line. Proteins vary widely in size, but are roughly an order of magnitude larger than metabolites.

Next are mRNAs. These long molecules diffuse slowly. They easily get caught up in other molecules. Most mRNAs reside in the cytoplasm, where they're translated. Fewer remain in the nucleus for processing and export.

The largest and slowest diffusing molecules would be the large protein-protein complexes and protein-RNA complexes, including ribosomes. But unlike slow diffusing mRNAs, they're globular rather than linear.

Together, these molecules form a system in which interactions are random but useful outcomes for the cell are not.

Compartments

Interactions don’t occur uniformly across the cell.

After this constant motion, the next thing we'd notice would be membrane barriers all around us. These are the outer surfaces of organelles: the nucleus, endoplasmic reticulum (ER), Golgi apparatus, vesicles, and lysosomes.

Organelle membranes do more than just divide space. They create unique local environments.

Lysosomes maintain acidic interiors that allow them to break down molecules. Mitochondria preserve a proton gradient that drives ATP production. The ER provides the right conditions for protein folding, while the Golgi offers an environment conducive to protein modification and sorting.

In each case, the barrier makes it possible for a specific job to be carried out under optimal conditions.

Yet, as well organized as this all sounds, there is no awareness, no master plan, and no master planner. All of these compartments arose from local interactions, as molecules spontaneously assembled into stable structures.

The nucleus and the genome

From our vantage point in the cell, the nucleus would likely appear as the largest bounded compartment, located near the center of the cell.

The nucleus is the home of the genome--the set of all 46 chromosomes (two sets of 23 chromosomes) that provide our genetic inheritance. This book's focus is genome replication. So let's cheat a bit and discuss the nucleus, even if we can't see inside.

During most of the cell cycle, genomic DNA exists in the form of chromatin--a loosely organized complex of DNA wrapped around protein spools called histones. It's not condensed into visible chromosomes. It's open and accessible.

Don't think of the nucleus as just a genome storage vault. The nucleoplasm is just as bustling as the cytoplasm. Proteins diffuse. Some bind and then unbind DNA. mRNAs are being synthesized. Large protein complexes are being assembled.

The nucleus is an active, crowded environment where molecules are constantly interacting with DNA and with each other.

Adding to this motion, the genome itself is not a rigid structure--it's dynamic and flexible and constantly being accessed, modified, and moved.

As with the rest of the cell, in the nucleus there is no central system deciding which part of the genome to use. Different regions of the genome are accessed locally as proteins encounter and bind to specific sequences.

So far, we’ve seen a system that is crowded, dynamic, and driven by constant motion. And yet, none of this explains how the cell achieves anything at all.

To understand that, we need to look closely at the molecules that do the work.