What Is Life?

by Paul Nurse

  Most enzymes are made from proteins, which are built by the cell as long, chain-like molecules called polymers. Polymer structures are fundamentally important for every aspect of life’s chemistry. As well as most enzymes and all other proteins, all the lipid molecules that make up cell membranes, all the fats and carbohydrates that store energy, and the nucleic acids responsible for heredity, deoxyribonucleic acid (DNA) and the closely related ribonucleic acid (RNA), are all polymers.

  These polymers are built principally from the atoms of just five chemical elements: carbon, hydrogen, oxygen, nitrogen and phosphorus. Of these five, carbon plays a particularly central role, largely because it is more versatile than the other elements. Whereas hydrogen atoms, for example, make only one connection – that is, a chemical bond – with other atoms, each carbon atom can bond to four other atoms. This is the key to carbon’s polymer-making abilities: two of carbon’s four potential bonds can be linked to two other atoms, often other carbon atoms, creating a chain of linked atoms – the core of each polymer. That leaves each carbon with two further bonds available to link with other atoms. These extra bonds can then be used to add other molecules to the sides of the main polymer chain.

  Many of the polymers found in cells are very large molecules, so large, in fact, that they are given a special name: macromolecules. To get a sense of quite how big these molecules can be, remember that the DNA macromolecules at the core of each of your chromosomes can be several centimetres long. That means they incorporate millions of carbon atoms into an incredibly long, but incredibly slender, molecular thread.

  Protein polymers are not so long, generally being based on a few hundred to several thousand linked carbon atoms. However, they are far more chemically variable than DNA, which is the main reason they can work as enzymes and therefore play a dominant role in metabolism. Each protein is a carbon-based polymer built by joining smaller amino acid molecules together, one at a time, into a long chain. Invertase, for example, is a protein molecule made by linking together 512 amino acids in a specific, ordered sequence.

  Life uses twenty different amino acids. Each of these amino acids have side molecules, branching off from the main polymer chain, that grant them distinct chemical properties. For example, some amino acids have positive or negative charges, others are either attracted to or repelled by water, and some are capable of easily forming bonds with other molecules. By stringing together different combinations of amino acids, each with different side molecules, cells can create a huge range of different protein polymer molecules.

  Then, once these linear protein polymer chains are assembled, they fold, twist and combine together to create complex three-dimensional structures. It’s a bit like the way a length of sticky tape can wrap itself up into a tangled ball, although the way proteins fold up is a much more repeatable process that generates a very precise structure. In a cell, the same string of amino acids will always try to form the same specific shape. This leap from the one-dimensional to three-dimensional is crucial, since it means each protein has a distinctive physical shape and a unique set of chemical properties. As a result cells can build enzymes in such a way that they fit together very precisely with the chemical substances they work on – parts of the invertase and sucrose molecules are a perfect fit, for example. This in turn allows enzymes to provide the precise chemical conditions needed to bring about specific chemical reactions.

  Enzymes execute almost all the chemical reactions that form the basis of cellular metabolism. But as well as building other molecules up and breaking them down, they play many other roles too. They act as quality controllers, they ferry components and messages between different regions of the cell, and they transport other molecules in and out of the cell. Others still are on the lookout for invaders, activating the proteins that defend cells and therefore our bodies from disease. And enzymes are not the only type of protein. Nearly every part of our bodies – from the hairs on our heads to the acid in our stomachs and the lenses in our eyes – are either made from protein, or are constructed by proteins. All these different proteins have been honed by millennia of evolution to fulfil specific functions within the cell. Even a relatively simple cell contains a huge number of protein molecules. In total, there are over 40 million of them in a tiny yeast cell; that’s twice as many proteins in a minuscule cell as there are people in a gigantic city like Beijing!

  The outcome of all of this protein diversity is a maelstrom of chemical reactions being carried out in every cell at all times. If you could imagine looking inside a living cell with eyes that could perceive the molecular world, your senses would be assaulted by a boiling tumult of chemical activities. Some of the molecules involved are electrically charged, making them either sticky or repellent, while others are passively neutral. Some are acids or bleach-like alkalis. All of these different substances are constantly interacting, either through random collisions or stage-managed meetings. Sometimes molecules come together transiently to react chemically, through a quick exchange of electrons or protons. At other times molecules remain chemically connected through the formation of tight and enduring bonds. Altogether, the cell contains many thousands of different chemical reactions that are constantly working away to sustain life. The number of chemical reactions used in even the largest industrial chemical plant pales in comparison. A plastics factory, for example, might be based on a few tens of chemical reactions.

  All this frantic and fast activity occupies the opposite end of the time spectrum from the deep time that was needed for these systems to evolve. But the dizzying timescale of the cellular world is just as challenging for our brains to comprehend as evolutionary time. Some of the cell’s enzymes that control these reactions work at an astonishingly fast rate, rattling through thousands, even millions, of chemical reactions every second. These enzymes are not only extremely rapid, but can also be extremely precise. They can manipulate individual atoms with a level of accuracy and reliability that chemical engineers can only dream of. But then evolution has been working to refine these processes for billions of years – rather longer than us humans!

  Making all this work together is an extraordinary achievement. Although the vast array of chemical reactions that occur simultaneously in cells may appear chaotic, it is in fact very highly ordered. For them to function properly, each of the different reactions requires its own particular chemical conditions. Some require more acid or alkaline surroundings; others demand particular chemical ions like calcium, magnesium, iron or potassium; others need or are slowed down by the presence of water. Yet somehow all these different chemistries must be carried out both simultaneously and very close together in the narrow confines of the cell. This is only possible because the various enzymes do not each require different extreme temperatures, pressures or acid or alkaline conditions, such as those found in industrial chemical facilities. If they did, they would not all be able to co-exist in such close proximity. Many of these metabolic reactions still need to be kept separate from one another, however. They must not interrupt each other, and all their specific chemical requirements must be met. Key to answering this challenge is compartmentation.

  Compartmentation is a way to get complex systems of all kinds to work. Take cities. They only work efficiently if they are organized into different compartments with particular functions: railway stations, schools, hospitals, factories, police stations, power stations, sewage disposal plants, and so on. All of these and much more are required for the city to work as a whole, but everything would break down if they were all completely mixed up together. They have to be separate to work effectively, but they also need to be relatively close together and connected. It is just the same for cells, which need to create a distinct set of chemical micro-environments that are separated from each other, either in physical space or across time, but also connected. Living things achieve this by constructing systems of interacting compartments that exist at a range of scales, from the very large to the extremely small.

  The
biggest of these scales will probably be most familiar: the different tissues and organs of multicellular organisms like plants, and animals – like you and me. These are distinct compartments, each customized for specific chemical and physical processes. Your stomach and intestines digest the chemicals in food; your liver detoxifies chemicals and drugs; your heart uses chemical energy to pump blood, and so on. The functions of these organs all depend on the specialized cells and tissues they are made from: cells in the stomach’s lining secrete acid, while those in the heart muscles contract. All those cells are, in turn, compartments in their own right.

  In fact, the cell is the fundamental example of the compartmentation of life. The essential role of the cell’s outer membrane is to keep the contents of the cell separate from the rest of the world. Thanks to the isolating effect of that membrane, cells can work to maintain an island of chemical and physical order. Cells can only sustain this state temporarily, of course: when they stop working, they die and chaos reasserts its grip.

  The cell itself contains successive layers of compartmentation. The largest of these compartments are the membrane-bounded organelles, such as the nucleus and the mitochondria. But before we can see how these work, we need to first zoom down to the simpler level of the carbon polymers, since the bigger compartments are all built on and around the properties of these elementary components.

  The smallest chemical compartments within the cell are the surfaces of the enzyme molecules themselves. To get a feeling for quite how small these molecules are, look at the very fine hairs on the back of your hand. They are among the most slender structures you can see with your naked eye, but they are massive compared to enzyme proteins. Around two thousand molecules of invertase could line up side by side across the diameter of each of those hairs.

  Each enzyme protein molecule provides enclosed spaces and docking sites which have specific shapes that are tailor-made, at the scale of individual atoms, for associating with the specific molecules that they work with. These exquisite structures are far too small to see directly, even with the most powerful light-focusing microscopes. Researchers must infer their shapes and properties using techniques such as X-ray crystallography and cryo-electron microscopy, which extend our senses to an extraordinary degree, allowing us to determine the positions and properties of the hundreds or thousands of connected atoms they are made from. Researchers can then see how enzymes interact with the chemicals they manipulate during a reaction. These chemicals are called substrates. Enzymes and their substrates fit together like the pieces of a minute three-dimensional jigsaw puzzle. When elements of this puzzle come together, the chemical reactions are shielded from the rest of the cell and presented at just the right angle and in the right chemical conditions for the enzymes to undertake their extraordinarily precise acts of atomic surgery, manipulating individual atoms and making or breaking particular molecular bonds. Invertase, for example, works by breaking one specific bond between an oxygen atom and a carbon atom in the middle of a molecule of sucrose.

  Enzymes are able to work together to ensure that the product of one reaction is passed on directly to become the substrate for the next. That way, a whole series of chemical reactions needed for complex processes, such as those needed to build lipid membranes or other complex chemical components from simpler constituents, can be co-ordinated. Biologists call these complex interacting series of chemical processes metabolic pathways, some of which involve many distinct reactions. They work rather like the assembly lines in a factory; each stage must be completed before the action moves on to the next.

  Enzymes can also work together to carry out even more complex acts of synthesis, like copying DNA with extraordinary precision. The enzymes that work like this are best imagined as absolutely tiny molecular machines which are extremely accurate and reliable in their operation. Some of these molecular machines use chemical energy to do physical work in the cell. These include proteins that act as molecular ‘motors’, powering most movement of cells themselves and of various cargoes and structures within cells. Some function like despatch drivers, carrying cellular components and chemicals to the part of the cell where they are needed. They do this by following the complex trackways, also made from proteins, that criss-cross the cellular interior rather like an elaborately branching railway network. Researchers have made films of these minute molecular motors in action, and seen them ‘walking’ around the cell like tiny robots. These motors have ratchet mechanisms, that keep them moving forward, and help them avoid being knocked off course by accidental collisions with other molecules.

  Versions of these molecular motors also create the forces needed to separate chromosomes and cleave dividing cells in half. And although they are each infinitesimally small, by working together in their billions, across many millions of muscle cells, these molecular motors are the things that power the wings of yellow butterflies as they flutter through our gardens, allow your eyes to follow the words on this page, and enable cheetahs to run at extraordinary speeds. Combining the tiny effects of individual proteins, working in very large numbers across many cells, leads to the real-world consequences we see all around us.

  At a somewhat larger scale than individual enzymes and molecular machines, groups of proteins can dock with each other physically, to form a set of cellular devices that orchestrate more complex chemical processes. Important among these are the ribosomes, which are where proteins are made. Each ribosome is made from several dozen proteins, together with several large molecules of RNA, DNA’s close chemical cousin. Ribosomes are bigger than the typical enzyme – they’d line up a few hundred, rather than several thousand, abreast across a hair’s breadth, but are still far too small to see directly, without the aid of an electron microscope. Cells that are growing and reproducing have a huge demand for new proteins, so they can each contain several million ribosomes.

  To build a new protein molecule, a ribosome must read the genetic code of a specific gene and translate it into the twenty-letter amino acid alphabet of proteins. To do this, the cell first makes a temporary copy of a specific gene. This copy is made from RNA. It acts as a messenger, and is indeed called messenger RNA, since it is physically transported from the genes in the nucleus to the ribosome, taking a copy of the gene’s information with it. The ribosome uses the messenger RNA as a template to build the protein, by stringing together amino acids in the order dictated by the gene. By forming a separate and highly structured micro-environment, ribosomes ensure this multistage, multi-enzyme process occurs accurately and rapidly: it takes only about a minute for each ribosome to build an average protein, consisting of 300 or so amino acids.

  Much bigger than ribosomes, although still truly minute compared to familiar human-scale objects, are the cell’s organelles, each contained within their own lipid membrane wrapper. These provide the next critical layer of compartmentation in eukaryote cells. At the heart of each of these cells is the organelle we know as the nucleus. Down a microscope the nucleus is usually the most visible of the organelles. But if most cells are small – two or three of your body’s white blood cells would line up across the breadth of those fine hairs on your hands – nuclei are smaller. Each one occupies only around 10% of the volume of a white blood cell. But remember, packed into that incredibly tiny space is an entire copy of all of your DNA, including all of your 22,000 genes – 2 metres of it in all when stretched out straight.

  All the different chemical activity that keeps cells alive requires energy, in fact lots of energy. Today, the great majority of life forms around us ultimately derive their energy from the sun. This is what the chloroplast, another organelle critical for life, achieves. Unlike the nucleus, these don’t exist in animal cells; they are found only in plants and algae. Chloroplasts are the sites of photosynthesis: the set of chemical reactions that uses energy from sunlight to drive the transformation of water and carbon dioxide into sugar and oxygen.

  The enzymes needed for photosynthesis are arranged within the two layers
of membrane that surround each chloroplast. Each of the cells in the blades of grass in your local park accommodates a hundred or so of these roughly spherical organelles, all of which contain high levels of proteins called chlorophylls. These chlorophylls are the reason grass looks green: they absorb energy from the blue and red parts of the spectrum of light, using it to power photosynthesis, resulting in them reflecting the green wavelengths.

  The plants, algae and some bacteria that can carry out photosynthesis use the simple sugars they produce as an immediate source of energy and as a raw material for building other molecules they need to survive. They also produce the sugars and carbohydrates that are consumed by so many other organisms: the fungi that feed on decaying wood, the sheep that nibble on grass, the whales that hoover up tons of photosynthesizing plankton in the sea, and all the food crops that sustain people on every continent of our world. In fact, the carbon that is so crucial for the construction of every part of our bodies comes ultimately from photosynthesis. It starts as carbon dioxide, which is drawn out of the air by the chemical reactions of photosynthesis.

  The chemistry of photosynthesis has not only provided the energy and raw material to build most of the life on Earth today, it has also played a definitive role in shaping our planet’s history. Life seems to have first appeared around 3.5 billion years ago, which is the age of the oldest fossils so far discovered. These were single-celled microbes, which probably derived their energy from geothermal sources. Because there was no photosynthesis during the earliest period of life on Earth, there was no major source of oxygen. As a result, there was almost no oxygen in the atmosphere, and when the planet’s early life forms did encounter oxygen it would have caused them problems.

  Although we think of oxygen as life-sustaining, as indeed it is, it is also a highly chemically reactive gas which can damage other chemicals, including the polymers essential for life, such as DNA. Once microbes evolved the ability to photosynthesize, they multiplied, over the millennia, to such an extent that the amount of oxygen in the atmosphere spiked. What followed, between 2 and 2.4 billion years ago, is called the Great Oxygen Catastrophe. All organisms that existed at that time were microbes, either bacteria or archaea, but some researchers think most of them were wiped out by the appearance of all that oxygen. It is ironic that life created conditions that nearly ended life as a whole. The minority of life forms that survived would have either retreated to places where they were less exposed to oxygen, perhaps at the bottom of the sea or deep underground, for example, or they had to adapt and evolve new chemistries needed to thrive in an oxygenated world.