by Paul Nurse
Today, organisms like us humans still handle oxygen with care, but we entirely depend on it because we need it to release energy from the sugars, fats and proteins that our bodies eat, make or absorb. This is brought about by a chemical process called cellular respiration. The final stages of this set of reactions take place within mitochondria: another organelle compartment that is critically important for all eukaryote cells.
The principal role of mitochondria is to generate the energy that cells need to power the chemical reactions of life. That’s why cells that need a lot of energy contain a lot of mitochondria: to keep your heart beating, each of the cells in the muscles of your heart must employ several thousand mitochondria. All together they occupy about 40% of the space available in those heart cells. In strictly chemical terms, cellular respiration reverses the reaction at the core of photosynthesis. Sugar and oxygen react with each other to make water and carbon dioxide, releasing a lot of energy, which is captured for later use. The mitochondria ensure this multi-step chemical reaction is highly controlled and takes place in an orderly, stepwise way, without too much energy being lost, and without reactive oxygen and electrons escaping and damaging the rest of the cell.
The key energy-capturing step in cellular respiration is based on the movement of protons, which are single atoms of hydrogen that have been stripped of an electron to give them an electrical charge. These protons are pushed out from the centre of the mitochondrion, into the gap between the two membranes that enclose each mitochondrion. This results in the build-up of many more charged protons outside the inner mitochondrial membrane than inside. Although based on chemistry, this is essentially a physical process. You can think of it as being rather like pumping water uphill to fill a dam. In a hydroelectric power station, water from the dam is allowed to rush downhill, through turbines that turn the water’s kinetic energy into electric energy. In the case of the mitochondria, protons pumped beyond the membrane ‘dam’ rush back into the centre of the organelle, via channels made of protein, which capture the force created by the cascade of charged particles and store it in the form of high-energy chemical bonds.
The person who first imagined that cells might produce their energy in such an unexpected way was the British biochemist and Nobel laureate Peter Mitchell. He used to be in the Zoology Department of the University of Edinburgh, where I later worked on the yeast cell cycle, but by the time I got there, he had left to set up his own private laboratory on the moors of south-west England. This was quite an unusual thing to do, and he was considered by some to be a true British eccentric. I met him when he was in his late seventies and was impressed by his unabated curiosity and passion for knowledge. Our conversations went everywhere. I was struck by the creativity of his thinking, and impressed by the way he ignored his doubters and went on to prove that his unusual idea was, in fact, correct.
The tiny protein structures that act as the ‘turbines’ in the mitochondria even look a bit like the turbines in electric power stations, although they are miniaturized by a factor of several billion-fold! As protons rush through the molecular turbine, which has a channel only 10 thousandths of a millimetre wide, they turn an equally small molecular-scale rotor. That turning rotor drives the generation of an all-important chemical bond, creating a new molecule of a substance called adenosine triphosphate, or ATP for short. This happens at the rapid rate of 150 reactions per second.
ATP is life’s universal energy source. Each molecule of ATP stores energy, acting like a minuscule battery. When a chemical reaction within a cell needs energy the cell breaks ATP’s high-energy bond, turning ATP into adenosine diphosphate (ADP), a process that releases energy that the cell can use to trigger a chemical reaction or a physical process, such as each of the steps taken by a molecular motor.
Most of the food you eat eventually ends up being processed in your cells’ mitochondria, which use the chemical energy it contains to make a prodigious quantity of ATP. To fuel all of the chemical reactions needed to support your body’s trillions of cells, your mitochondria together produce, amazingly, the equivalent of your entire bodyweight in ATP every day! Feel the pulse beating in your wrist, the heat of your skin, and the rise and fall of your chest as you breathe: it’s all fuelled by ATP. Life is powered by ATP.
All living things need a constant and reliable supply of energy and, ultimately, they all make their energy through the same process: controlling the flow of protons across a membrane barrier to make ATP. If there is anything remotely like a ‘vital spark’ that sustains life, it is perhaps this tiny flow of electric charge across a membrane. But there is nothing mystical about it: it is a well-understood physical process. Bacteria do this by actively pumping protons across their outer membrane, while the more complex cells of eukaryotes do it within a specialized compartment: the mitochondrion.
Together, all of these different levels of spatial organization within cells – from the unimaginably small docking sites within individual enzymes, to the comparatively large nucleus that contains the chromosomes – point to a new way of thinking about the cell. When we look at the beautiful and highly elaborate pictures produced by the powerful microscopes of today, we are looking at a complex and constantly changing network of organized and interconnected chemical micro-environments. This view of the cell is worlds away from that of cells as mere Lego-like building blocks for the more complex tissues and organs of plants and animals. Each cell is a complete and highly sophisticated living world in its own right.
Gradually, since Lavoisier started to ask how fermentation worked more than two centuries ago, biologists have come to recognize that even the most complex behaviours of cells and of multicellular bodies can be understood in terms of chemistry and physics. This way of thinking was very important to me and my lab colleagues as we sought to understand how the cell cycle is controlled. We had discovered the cdc2 gene as a cell cycle controller, but we then wanted to know what the gene actually did. What chemical or physical processes does the Cdc2 protein it makes actually carry out?
To work this out we needed to move from the rather abstract world of genetics to the more concrete, mechanistic world of cellular chemistry. That meant we had to do biochemistry. Biochemistry tends to take a more reductionist approach, describing chemical mechanisms in great detail, whilst genetics takes a more holistic approach, looking at the behaviour of the living system as a whole. In our case, genetics and cell biology had shown us that cdc2 was an important controller of the cell cycle, but we needed biochemistry to show how the protein made by the cdc2 gene worked in molecular terms. Both approaches provide different kinds of explanations; when they agree with each other it gives you confidence that you are on the right track.
It turned out that the Cdc2 protein was an enzyme called a protein kinase. These enzymes catalyze a reaction called phosphorylation that adds a small phosphate molecule, which has a strong negative charge, to other proteins. For Cdc2 to function as a protein kinase it must first bind to another protein called cyclin, which activates it. Together, Cdc2 and cyclin form an active protein complex called Cyclin Dependent Kinase, or CDK for short. Cyclin was discovered and named by my friend and colleague Tim Hunt, as a protein that ‘cycled’ up and down in level through the cell cycle, with those changes being part of the mechanism the cell uses to ensure the CDK complex is turned ‘on’ and ‘off’ at the correct time. Cyclin, incidentally, is a much better name than cdc2!
When the active CDK complex phosphorylates other proteins, the negatively charged phosphate molecule that it adds changes the shape and chemical properties of those target proteins. That, in turn, changes the way they work. It can, for example, activate other enzymes, just as adding cyclin to the Cdc2 protein makes active CDK. Because protein kinases like CDK can rapidly phosphorylate many different proteins simultaneously, these enzymes are often used as switches in cells. That is what happens in the cell cycle. Processes such as copying the DNA in S-phase, early in the cell cycle, and separating the copied chromosome
s during mitosis, late in the cell cycle, demand the co-ordinated action of many different enzymes. By phosphorylating large numbers of these different proteins all at once, CDK can exert control over complex cellular processes. Understanding protein phosphorylation is, therefore, key to understanding cell cycle control.
I cannot stress enough how satisfying it was to work all of this out and really see how cdc2 exerted its great influence over the cell cycle. It really did feel like one of those rare eureka moments. The programme of research in my lab had moved from identifying genes in yeast, such as cdc2, which controlled the cell cycle and therefore cell reproduction, through to showing this control was the same in all eukaryotes from yeast to humans, to finally working out the molecular mechanism by which it acted. This took quite a long time though, a total of about fifteen years, with about ten colleagues working together in my lab. And, as is usually the case in science, it was also based on contributions from many other labs around the world, working on the cell cycle in cells from an exotic range of living organisms, including starfish, sea urchins, fruit flies, frogs, mice and, eventually, humans.
Ultimately, life emerges from the relatively simple and well-understood rules of chemical attraction and repulsion, and the making and breaking of molecular bonds. Somehow these foundational processes, operating en masse at a minuscule molecular scale, combine to create bacteria that can swim, lichens that grow on rocks, the flowers we tend in our gardens, flitting butterflies, and you and me, who are able to write and read these pages.
The notion that cells, and therefore living organisms, are astoundingly complicated, but ultimately comprehensible, chemical and physical machines is now the accepted way to think about life. Today, biologists build on this insight by attempting to characterize and catalogue all the components of these astonishingly complex living machines. To do this, we now have access to powerful technologies that allow deep study of the extreme complexity of living cells. We can take a cell or a group of cells and sequence all the DNA and RNA molecules they contain, and identify and count the thousands of different types of proteins present. We can also describe in detail all the fats, sugars and other molecules that are found in the cells. These technologies hugely extend the reach of our senses, giving us a new and highly comprehensive view of cells’ invisible and ever-changing componentry.
Opening these new vistas onto the cell creates new challenges too. As Sydney Brenner put it: ‘We are drowning in data but thirsty for knowledge.’ His concern was that too many biologists spend a lot of time recording and describing the details of living chemistry, without always fully understanding what it all means. Central to turning all this data into useful knowledge is understanding how living things process information.
This is the fifth of biology’s great ideas, and the one we will consider next.
5. LIFE AS INFORMATION
Working as a Whole
What was it that made that yellow butterfly venture into my childhood garden all those years ago? Was it hungry, looking for somewhere to lay its eggs, or perhaps being chased by a bird? Or was it just responding to some inbuilt urge to explore its world? Of course I do not know why that butterfly was behaving as it did, but what I can say is that it was interacting with its world and then taking action. And to do that, it had to manage information.
Information is at the centre of the butterfly’s existence and indeed at the centre of all life. For living organisms to work effectively as complex, organized systems they need to constantly collect and use information about both the outer world they live in and their internal states within. When these worlds – either outer or inner – change, organisms need ways to detect those changes and respond. If they do not, their futures might turn out to be rather brief.
How does this apply to the butterfly? When it was flying about, its senses were building up a detailed picture of my garden. Its eyes were detecting light; its antennae were sampling molecules of the different chemical substances in its vicinity; and its hairs were monitoring vibrations in the air. Altogether, it was gathering a lot of information about the garden I was sitting in. It then brought all this diverse information together, with the aim of transforming it into useful knowledge that it could then act upon. That knowledge might have been detecting the shadow of a bird or of an inquisitive child, or recognizing the smell of nectar from a flower. This then generated an outcome: an ordered sequence of wing movements that led the butterfly to either avoid the bird or to settle on a flower to feed. The butterfly was combining many different sources of information and using them to make decisions with meaningful consequences for its future.
Closely linked with their reliance on information is the way living things act with a sense of purpose. The information the butterfly was gathering meant something. It was being used by the butterfly to help it decide what to do next to achieve some specific end. That meant it was acting with purpose.
Biology is a branch of science where it can often make sense to talk about purpose. In the physical sciences by contrast we would not ask about the purpose of a river, a comet or a gravitational wave. But it does make sense to ask that of the cdc2 gene in yeast, or of the flight of a butterfly. All living organisms maintain and organize themselves, they grow, and they reproduce. These are purposeful behaviours that have evolved because they improve the chances of living things achieving their fundamental purpose, which is to perpetuate themselves and their progeny.
Purposeful behaviour is one of life’s defining features, but it is only possible if living systems operate as a whole. One of the first people to understand this distinctive feature of living things was the philosopher Emmanuel Kant, at the turn of the nineteenth century. In a book called Critique of Judgement, Kant argued that the parts of a living body exist for the sake of the whole being, and that the whole being exists for the sake of its parts. He proposed that living organisms are organized, cohesive and self-regulating entities that are in control of their own destiny.
Consider this at the level of the cell. Each cell contains a profusion of different chemical reactions and physical activities. Things would rapidly break down if all these different processes operated chaotically, or in direct competition with one another. It is only by managing information that the cell can impose order on the extreme complexity of its operations and therefore fulfil its ultimate purpose of staying alive and reproducing.
To understand how this works, remember that the cell is a chemical and physical machine that behaves as a whole. You can understand quite a lot about a cell by studying its individual components, but to function properly, the multitude of different chemical reactions operating within the living cell must communicate with each other and work together cohesively. That way, when either its environment or its inner state changes – perhaps the cell runs low on sugar, or encounters a poisonous substance – it can sense that change and adjust what it does, thereby keeping the whole system functioning as optimally as possible. Just as a butterfly gathers information about the world and uses this knowledge to modify its behaviour, cells are constantly assessing the chemical and physical circumstances both within and around them, and using that information to regulate their own state.
To get a better handle on what it means for cells to use information to regulate themselves, it might be helpful to first consider how it is achieved in more straightforward human-designed machines. Take the centrifugal governor, first developed for use with millstones by the Dutch polymath Christiaan Huygens, but adapted with great success by the Scottish engineer and scientist James Watt in 1788. This device could be fitted to a steam engine to ensure the engine runs at a constant speed, rather than racing away and perhaps breaking down. It is comprised of two metal balls that spin around a central axis, which is powered by the steam engine itself. As the engine runs faster, centrifugal forces push the balls outwards and upwards. This has the effect of opening a valve, which releases steam from the engine’s piston, slowing the steam engine down. As the engine slows, gravity pu
lls the steel balls of the governor back down, closing the valve and allowing the steam engine to speed up again, towards the desired speed.
We can understand Watt’s governor best in terms of information. The position of the balls act as a read-out for information about the speed of the engine. If that speed exceeds the desired level, then a switch is activated – the steam valve – which reduces the speed. This creates an information-processing device which the machine can use to regulate itself, without needing any input from a human operator. Watt had built a simple mechanical device that behaves in a purposeful way. Its purpose was to keep the steam engine operating at constant speed, and it achieved that purpose brilliantly.
Systems that work in a conceptually similar way, although often through very much more complex and adjustable mechanisms, are used widely in living cells. Such mechanisms provide an efficient way of achieving homeostasis, which is the active process of maintaining conditions that are conducive to survival. It’s through homeostasis that your body works to maintain a consistent temperature, fluid volume and blood sugar, for example.