What Is Life?

by Paul Nurse

  Whatever the source of genetic variability, to fuel evolutionary change it must persist during subsequent reproduction and generate populations of organisms that vary across every possible dimension, whether that’s subtle differences in disease resistance, attractiveness to mates, food tolerance, or any number of other characteristics. Natural selection can then act to sift the helpful variants from the harmful.

  One profound consequence of evolution by natural selection is that all life is connected by descent. This means that as the tree of life is traced backwards, the branches increasingly converge into bigger branches and eventually into a single trunk. The conclusion therefore, is that we humans are related to every other life form on the planet. To some, like the apes, we are closely related, because we are on adjacent twigs at the edge of the tree, and to others, like my yeast, the relationship is much more distant, because we only become ‘joined’ much further back in time, closer to the main trunk of the tree of life.

  Our fundamental connectedness to other life was brought home to me when I went trekking through the humid and verdant Ugandan rainforest, in search of mountain gorillas. Following my guide, we suddenly came upon a family group. I found myself sitting opposite a magnificent silverback, who was squatting underneath a tree, just two or three metres away from me. I broke out into a sweat, and it was not just because it was hot and humid. As a geneticist, I knew that he and I shared about 96% of our genes, but that bald number can only tell part of the story. As his intelligent, deep brown eyes locked my gaze, I saw many aspects of my humanity reflected back at me. Those apes were closely attuned to each other and also to us humans. Much of their behaviour was inescapably familiar; their empathy and curiosity obvious. The silverback and I contemplated each other for several minutes. It was like a conversation. Then he put out a hand, bent double a five-centimetre diameter sapling (was he trying to tell me something?) and slowly climbed the tree, all the time holding me in his gaze with those penetrating eyes. This dramatic and moving encounter emphasized for me quite how closely we are related to these magnificent creatures. That connectedness extends beyond the gorilla to other apes, to mammals and other animals, and even, via more ancient forks in life’s shared family tree, to plants and microbes. This, to me, is one of the best arguments for why humanity should care about the entire biosphere; all the different life forms that share our planet are our relatives.

  I became aware of our deep relatedness to other living things in an even more unexpected way when I decided to ask whether fission yeast and human cells controlled their cell cycles in the same way. I asked this question during the 1980s, when I found myself working in a cancer research institute in London. Since cancer is caused by aberrant cell division of human cells, most of my colleagues, working in other labs, very understandably, were much more interested to know what controlled the cell cycle in humans rather than in yeast. By that time I knew what controlled cell division in yeast: it was a cell cycle control mechanism with cdc2, that crucial gene with the uninspiring name, at its very centre.

  I wondered if it could possibly be the case that human cell division was also controlled by a human version of the same gene, cdc2? This seemed very unlikely, given that yeasts and humans are so very different and last had an ancestor in common 1.2 to 1.5 billion years ago (that is, 1,200 to 1,500 million years ago). To put that huge expanse of time in perspective, dinosaurs became extinct a ‘mere’ 65 million years ago, and the first simple animals appeared around 500–600 million years ago. If I’m completely honest, it was more than slightly preposterous to believe that such distant relatives could have cells whose reproduction was controlled in the same way. Nevertheless, we had to find out.

  The way Melanie Lee in my lab tackled this question was to try and find a human gene that functioned the same way as did cdc2 in fission yeast. To do this, she took fission yeast cells that were defective in cdc2 and so could not divide, and ‘sprinkled’ on them a gene ‘library’ that was made up of many thousands of pieces of human DNA. Each piece of DNA contained a single human gene. Melanie used conditions that ensured that the mutant yeast cell would usually only take up one or two genes. If it so happened that one of these genes was the human equivalent of the cdc2 gene and if it functioned in the same way in both human and yeast cells, and if the human cdc2 gene could get into the yeast cells, then the cdc2 mutant cells might just regain the ability to divide. If all that went right, they should form colonies that Melanie could see on a Petri dish. You may have noticed there were several ‘ifs’ in this plan. Did we think the experiment would work? Probably not, but it was worth a shot.

  And, amazingly, it did work! Colonies grew on the Petri dish and we were able to isolate the stretch of human DNA that had successfully stood in for the cdc2 gene that is so vital for yeast cell division. We sequenced this unknown gene and saw that the sequence of the protein it made was very similar to the yeast Cdc2 protein. It was obvious that we were looking at two highly related versions of the same gene. So similar were they that the human gene could control the yeast cell cycle.

  This unexpected result led us to a far-reaching conclusion. Given that fission yeast and humans are so distantly related in evolution, it was very likely that cells in every animal, fungus and plant on the planet controlled their cell cycle in the same way. They almost certainly all depended on the action of a gene that was very similar to yeast’s cdc2 gene. And, what is more, even as these different organisms gradually evolved over aeons of evolutionary time to take on countless different forms and lifestyles, the core controls of this most fundamental process had barely changed. Cdc2 is an innovation that has endured for more than one billion years.

  All of this reinforced my conviction that understanding how human cells control their division, which is crucial for understanding how our bodies change as we grow, develop, suffer diseases and degenerate across our lifespans, can be studied profitably in a wide range of living organisms, including the simple yeast.

  Natural selection not only takes place during evolution; it is also taking place at the level of the cells inside our bodies. Cancer starts when genes important for controlling the growth and division of cells are damaged or rearranged, leading to cells that divide in uncontrolled ways. Just like evolution within a population of organisms, these pre-cancerous or cancerous cells can, if they evade the body’s defences, gradually overtake the population of unaltered cells that make up the tissue. As the population of damaged cells grows, there is a greater chance of further genetic changes taking place within these cells, leading to an accumulation of genetic damage and the generation of increasingly aggressive cancerous cells.

  This system has the three characteristics necessary for evolution by natural selection: reproduction, a hereditary system, and the ability of the hereditary system to exhibit variability. It is paradoxical that the very circumstances that allowed human life to evolve in the first place are also responsible for one of the most deadly human diseases. More practically, it also means that population and evolutionary biologists should be able to contribute significantly to our understanding of cancer.

  Evolution by natural selection can bring about great complexity and the apparent purposefulness of living things. It does this without any controlling intellect, defined end goal, or ultimate driving force. It sidesteps completely the arguments invoking a divine Creator, as made by Paley with his imagined pocket watch, and many others before and since. And it leaves me, for one, in a state of constant wonder.

  Learning about evolution also had a rather dramatic impact on the course of my life. My grandmother was a Baptist, so we used to go to the local Baptist church every Sunday. I knew the Bible well (still do), and even had thoughts of becoming a minister, perhaps even a missionary! Then, around the time I saw that brimstone butterfly in my garden, I was taught about evolution by natural selection at school. The scientific explanation for life’s abundant diversity was clearly in direct conflict with the biblical account. Trying to make sense of this
discrepancy, I went to talk to my Baptist minister. I suggested to him that when God was speaking about the Genesis account of creation, he was explaining what happened in terms that would make sense to an uneducated, pastoral population two or three thousand years ago. I said that we should perhaps treat it more like a myth, but that, in reality, God had devised an even more wonderful mechanism for creation, by inventing evolution by natural selection. Unfortunately my minister did not see it like that at all. He told me I had to believe the literal truth of Genesis and said that he would pray for me.

  Thus began my gradual descent from religious belief to atheism, or to be more precise, sceptical agnosticism. I saw that different religions can have very different beliefs, and that those different creeds could be inconsistent with each other. Science gave me a route to a more rational understanding of the world. It gave me greater certainty too, stability even, and a better way to pursue truth; the ultimate objective of science.

  Evolution by natural selection describes how different life forms can come about and attain purpose. It is driven by chance and steered by the necessity of generating increasingly effective life forms. However, it does not give much insight into how living organisms actually work. For that we have to turn to the next two ideas, the first of which is life as chemistry.

  4. LIFE AS CHEMISTRY

  Order from Chaos

  Most people would probably look at the world around them and divide it into two main types of thing: those that are alive and those that are clearly not. Living organisms stand out because they are things of action; they behave with purpose, reacting to their surroundings and reproducing themselves. None of these characteristics apply to things that are not living, like a pebble, a mountain, or a sandy beach, for example. Indeed, if we were to step back in time a couple of hundred years, before the development of the ideas described in this book, we might well have concluded that earthly life is directed by mysterious forces that are unique to living things.

  This way of thinking is called ‘vitalism’, and its origins trace back to the classical thinkers Aristotle and Galen, and probably even further. Even for the most rational and scientific among us, it is hard to entirely abandon such thinking. If you’ve ever seen someone die, you will know it can seem very much as if some inexplicable spark of life has been abruptly extinguished.

  Vitalist explanations are appealing since they seem to provide a comforting solution to what our minds struggle to grasp. But we can in fact now be certain that we do not need to invoke any form of magic. Most aspects of life can be understood rather well in terms of physics and chemistry, albeit an extraordinary form of chemistry that is highly ordered and organized, and of a sophistication that cannot be matched by any inanimate process. For me, this explanation is more awe-inspiring than any kind of belief that life is directed by mysterious forces that lie beyond the reach of scientific scrutiny.

  This idea that life is chemistry rather surprisingly had its origins in studies of fermentation, the process by which the simple microbe yeast makes alcohol during the production of beer and wine. This has been a long-standing interest of humanity.

  In fact, my own life has been influenced quite a lot by fermentation, and not just because I am rather fond of beer myself; sitting alone contemplating the world in an empty pub early in the evening is a real pleasure. When I left school at seventeen years of age, I knew I wanted to study biology, but I couldn’t get a place at university. At that time a basic foreign language qualification, achieved via an exam known as an O-level, was a compulsory entry requirement for all undergraduate degree programmes, but I managed to fail my French exam six times, probably a world record in O-level failures! So I didn’t go to university, but went to work instead as a technician in a microbiology laboratory linked to a brewery.

  Part of my job each day was to make all the nutrient-containing concoctions that the scientists needed to grow their microbes. I soon realized that they nearly always placed the same daily order, so I could make it all up in a big batch on Monday, which would then last all week. I went to see my boss Vic Knivett (who, incidentally, was a Georgian dancer in his spare time, a fact I discovered when I found him one evening performing an energetic Cossack-like kicking dance on top of one of the laboratory benches!). Generously, he suggested I carry out a research project on Salmonella infections of hens’ eggs. I was an eighteen-year-old in heaven, doing experiments every day, pretending to be a real scientist.

  At some point during that year in the brewery, a sympathetic professor at Birmingham University called me for an interview, and eventually persuaded the university to overlook my weaknesses in foreign languages so I could start a biology degree in 1967. Ironically, considering my early struggles with the language, thirty-five years later I was granted an award called the Légion d’honneur by the President of France for my research on yeast. I even had to give my acceptance speech in French! However, despite studying yeast for most of my life, I have never made a drop of either wine or beer myself.

  The scientific study of fermentation began with the eighteenth-century French nobleman and scientist Antoine Lavoisier, one of the founders of modern chemistry. Unfortunately for him, and unfortunately for science as a whole, his part-time activities as a tax collector meant he lost his head in May 1794, during the French Revolution. The judge of the kangaroo political court that sentenced him declared that the ‘Republic has no need for savants and chemists’. We scientists obviously have to treat politicians with caution! There is an unfortunate tendency for politicians, especially those of a populist bent, to ignore ‘experts’, particularly when that expertise counters their poorly substantiated opinions.

  Before his untimely encounter with the guillotine, Lavoisier had become fascinated by the process of fermentation. He concluded that ‘fermentation was a chemical reaction in which the sugar of the starting grape juice was converted into the ethanol of the finished wine’. Nobody had thought about it in quite that way before. Then Lavoisier went further and proposed that there was something called a ‘ferment’, which seemed to come from the grapes themselves, which played a key role in the chemical reaction. He couldn’t say what this ‘ferment’ was, however.

  Things became clearer about half a century later, when the makers of industrial alcohol asked the French biologist and chemist Louis Pasteur to help them solve a mystery that kept destroying their products. They wanted to know why their fermentations of sugar beet pulp sometimes went wrong, producing a sour and unpleasant acid instead of ethanol. Pasteur embarked on this mystery as a detective might. Using a microscope, he obtained the crucial clue. Sediments in the fermentation vats that produced alcohol contained yeast cells. The yeast were clearly alive because some of them had buds, showing they were actively multiplying. When he looked into the soured vats he couldn’t see any yeast cells at all. From these simple observations, Pasteur proposed that the microbial life form yeast was the elusive ferment: the key agent responsible for making ethanol. Some other microbe, probably a smaller bacterium, generated the acid that ruined the failed batches.

  The point here was that the growth of living cells was directly responsible for a specific chemical reaction. In this case, the yeast cells were converting glucose into ethanol. The most important thing Pasteur did was to step from the specific to the general, to reach an important new conclusion. He argued that chemical reactions were not just an interesting feature of cellular life – they were one of life’s defining features. Pasteur summarized this brilliantly when he said that ‘chemical reactions are an expression of the life of the cell’.

  We now know that within the cells of all living organisms many hundreds, even thousands, of chemical reactions are being carried out simultaneously. These reactions build up the molecules of life, which form the components and structures of cells. They also break molecules down, to recycle cellular components and release energy. Together, the vast array of chemical reactions occurring in living organisms is called metabolism. It is the basis of ev
erything living things do: maintenance, growth, organization and reproduction, and the source of all the energy needed to fuel these processes. Metabolism is the chemistry of life.

  But how are all the many and varied chemical reactions that make up metabolism brought about? What type of substance was it in Pasteur’s yeast that was carrying out the chemical reactions of fermentation? Another French chemist, Marcelin Berthelot, delved deeper into this mystery and made the next advance. He pulverized yeast cells, and from the cellular remnants extracted a chemical substance which behaved in an intriguing way. It triggered a specific chemical reaction – the conversion of table sugar, sucrose, into its two smaller component sugars: glucose and fructose – but it was not itself consumed by the reaction. It was an inanimate substance but integral to a living process and, notably, it continued to work when it was removed from the cell. He called this new substance invertase.

  Invertase is an enzyme. Enzymes are catalysts: that means they facilitate and speed up chemical reactions, often dramatically. They are acutely important for life. Without them many of the chemical processes most vital for life would simply not happen, especially at the relatively low temperatures and mild conditions found within most cells. The discovery of enzymes laid the foundations for today’s consensus view – shared by all biologists – that most phenomena of life can be best understood in terms of chemical reactions that are catalyzed by enzymes. To understand how enzymes achieve this we need to understand what they are and how they are made.