What Is Life?

by Paul Nurse

  Growth, repair, degeneration and malignancy are all linked to changes in the properties of our cells, in sickness and in health, in youth and in old age. In fact, most diseases can be traced back to the malfunction of cells, and understanding what goes wrong in cells underpins how we develop new ways to treat disease.

  Cell theory continues to influence the trajectory of research in the life sciences and in medical practice. It drastically shaped the course of my life too. Ever since my thirteen-year-old self squinted down a microscope and saw the cells of that onion root tip, I have been curious about cells and how they work. When I started as a biology researcher, I decided to study cells, in particular how cells reproduce themselves and control their division.

  The cells I started to work with in the 1970s were yeast cells, which most people think are only good for making wine, beer or bread, not for tackling fundamental biological problems. But they are, in fact, a great model for understanding how cells of more complex organisms work. Yeast is a fungus, but its cells are surprisingly similar to plant and animal cells. They are also small, relatively simple, and grow quickly and inexpensively when fed on simple nutrients. In the lab we grow them either floating freely in a liquid broth or on top of a layer of jelly in a plastic Petri dish, where they form cream-coloured colonies a few millimetres across, each containing many millions of cells. Despite, or more accurately, because of their simplicity, yeast cells have helped us to understand how cells divide in most living organisms, including human cells. Quite a lot of what we know about the uncontrolled cell divisions of cancer cells came first from studying the humble yeasts.

  Cells are the basic unit of life. They are individual living entities, surrounded by membranes made from fat-like lipids. But, just as atoms contain electrons and protons, cells contain smaller components too. Microscopes today are very powerful and biologists use them to reveal the intricate and often very beautiful structures within cells. The largest of these structures are called organelles, which are each wrapped in their own layer of membrane. Of these, the nucleus is a command centre of the cell, since it contains the genetic instructions written into the chromosomes, while mitochondria – and there can be hundreds of these in some cells – act as miniature power plants, supplying the cell with the energy it needs to grow and survive. A variety of other containers and compartments within cells perform sophisticated logistics functions, building, breaking down or recycling cellular parts, as well as shuttling materials in and out of the cell and transporting them around the cell’s interior.

  Not all living organisms are based on cells that contain these membrane-bounded organelles and complex internal structures, however. The presence or absence of a nucleus divides life into two major branches. Those organisms whose cells contain a nucleus – such as animals, plants and fungi – are called eukaryotes. Those without a nucleus are called prokaryotes, which are either bacteria or archaea. Archaea appear to be similar to bacteria in terms of their size and structure but are actually their distant relatives. In some respects their molecular workings are more similar to eukaryotes like us, than they are to bacteria.

  A critically important part of a cell, be it a prokaryote or a eukaryote, is its outer membrane. Although just two molecules thick, this outer membrane forms a flexible ‘wall’ or barrier that separates each cell from its environment, defining what is ‘in’ and what is ‘out’. Both philosophically and practically, this barrier is crucial. Ultimately, it explains why life forms can successfully resist the overall drive of the universe towards disorder and chaos. Within their insulating membranes, cells can establish and cultivate the order they need to operate, whilst at the same time creating disorder in their local surroundings outside the cell. That way life does not contravene the Second Law of Thermodynamics.

  All cells can detect and respond to changes in their inner state and in the state of the world around them. So although separated from the environment they live in, they are in close communication with their surroundings. They are also constantly active and working to maintain the internal conditions that allow them to survive and to flourish. They share this with more visible living organisms, such as the butterfly I watched as a child, or for that matter with ourselves.

  In fact, cells share many characteristics with all kinds of animals, plants and fungi. They grow, they reproduce, they maintain themselves, and in doing all of this they display a sense of purpose: an imperative to persist, to stay alive and to reproduce, come what may. All cells, from the bacteria Leeuwenhoek found between his teeth to the neurons that allow you to read these words, share these properties with all living beings. Understanding how cells work brings us closer to understanding how life works.

  Core to the existence of the cell are the genes, which we will turn to next. These encode instructions that each cell uses to build and organize itself, and they must be passed to every new generation when cells and organisms reproduce.

  2. THE GENE

  The Test of Time

  I have two daughters and four grandchildren. All of them are wonderfully unique. For example, one of my daughters, Sarah, is a TV producer and the other, Emily, a professor of physics. But there are also characteristics that they share between themselves, their children, with me, and my wife Anne. Family resemblances can be strong or subtle – height, eye colour, the curve of the mouth or nose, even particular mannerisms or facial expressions. There are many variations too, but the continuity between generations is undeniably there.

  The existence of similarities between parents and offspring is a defining characteristic of all living organisms. It was something that Aristotle and other classical thinkers recognized long ago, but the basis of biological inheritance remained a stubborn mystery. Various explanations were given over the years, some of which sound a bit peculiar today. Aristotle, for example, suspected that mothers only influenced the development of their unborn children in the same way that the qualities of a particular soil influenced the growth of a plant from a seed. Others thought that the explanation was ‘blending of the blood’; that is the idea that children inherit an average mixture of their two parents’ characteristics.

  It took the discovery of the gene to pave the way to a more realistic understanding of how inheritance works. As well as providing a way to help make sense of the complicated mixture of resemblances and unique characteristics that run through families, genes are the key source of information life uses to build, maintain and reproduce cells and, by extension, organisms made from cells.

  Gregor Mendel, Abbot of Brno Monastery, now in the Czech Republic, was the first person to make some sense of the mysteries of inheritance. But he didn’t do this by studying the often baffling patterns of inheritance in human families. Instead, he carried out careful experiments with pea plants, hatching the ideas that led eventually to the discovery of the things we now call genes.

  Mendel wasn’t the first person to use scientific experiments to ask questions about inheritance, nor even the first to use plants to look for answers. These earlier plant breeders had described how some characteristics of plants were passed through the generations in counterintuitive ways. The offspring of a cross between two different parental plants would sometimes look like a blend between the two of them. For example, crossing a purple-flowered plant and a white-flowered plant might give rise to a pink-flowered plant. But other characteristics always seemed to dominate in a particular generation. In these situations, the offspring of a purple-flowered plant and a white-flowered plant would all have purple flowers, for example. The early pioneers had gathered lots of intriguing clues, but none of them had managed to reach a satisfying understanding of how genetic inheritance operates in plants, let alone explain how it works in essentially all living things, including us humans. That, however, is exactly what Mendel started to reveal with his work on peas.

  In 1981, in the middle of the Cold War, I went on my own pilgrimage to the Augustinian monastery in Brno to see where Mendel worked. This was long before
it had become the tourist attraction that it is today. The garden, then rather overgrown, was surprisingly big. I could easily imagine the rows upon rows of peas that Mendel once grew there. He had studied physical sciences at the University of Vienna but failed to qualify as a teacher. However, something from his training in physics stuck with him. He clearly understood that he would need a lot of data: big samples are more likely to uncover important patterns. Some of his experiments involved 10,000 different pea plants. None of the plant breeders before him had taken such a rigorous, extensive quantitative approach.

  To reduce the complexity of his experiments, Mendel focused only on characteristics that displayed clear-cut differences. Over several years, he carefully recorded the outcomes of the crosses he set up, and detected patterns that others had missed. Most importantly, he observed distinctive arithmetic ratios of pea plants that either exhibited or lacked specific characteristics, such as particular flower colours or seed shapes. One of the crucial things Mendel did was to describe these ratios in terms of a mathematical series. This led him to propose that the male pollen and female ovules within the pea flowers, contain things he called ‘elements’ that are associated with the different characteristics of the parental plants. When these elements come together through fertilization they influence the characteristics of the next generation of plants. However, Mendel did not know what the elements were or how they might work.

  By intriguing coincidence, another famous biologist, Charles Darwin, was studying plant crosses with flowers called snapdragons at around the same time as Mendel. He observed similar ratios, but did not try and interpret what they might mean. In any case, Mendel’s work was almost entirely ignored by his contemporaries and it was another whole generation before anyone took him seriously.

  Then, around 1900, other biologists working independently repeated Mendel’s results, developed them further, and started making more explicit predictions about how inheritance might work. This work led to the theory of Mendelism, named in the pioneering monk’s honour, and the birth of genetics. Now the world began to take notice.

  Mendelism proposes that inherited characteristics are determined by the presence of physical particles, which exist as a pair. These ‘particles’ are what Mendel called ‘elements’ and we now call genes. Mendelism did not have much to say about what these particles were, but it described in a very precise way how they are inherited. And most crucially, it gradually became clear that these conclusions not only applied to peas, but to all sexually reproducing species, from a yeast to humans and all organisms in between. Every one of your genes exists as a pair; you inherited one from each of your biological parents. They were transmitted through the sperm and egg that fused together at the moment of your conception.

  Science had not stood still during the final third of the nineteenth century when Mendel’s discoveries had lain fallow. In particular, researchers had finally managed to get a clearer view of cells engaged in the process of cell division. When these observations were eventually linked to the inherited particles proposed by Mendelism, the gene’s central role in life came into a sharper focus.

  An early clue was the discovery of microscopic structures within cells that looked like tiny threads. These were first spotted in the 1870s by a German military physician turned cell biologist called Walther Flemming. Using the best microscopes of his day, he described how these microscopic threads behaved in an intriguing way. As a cell got ready to divide, Flemming saw these threads splitting in half lengthwise, before becoming shorter and thicker. Then, when the cell divided into two, the threads were separated, with one half ending up in each of the newly formed daughter cells.

  What Flemming was looking at, but did not fully understand at the time, was the physical manifestation of the genes, the inheritable particles proposed by Mendelism. What Flemming called ‘threads’, we now call chromosomes. Chromosomes are the physical structures present in all cells that contain the genes.

  Around the same time, another crucial clue about genes and chromosomes emerged from an unlikely source: the fertilized eggs of parasitic roundworms. When the Belgian biologist Edouard van Beneden examined carefully the very earliest stages of roundworm development, he saw through his microscope that the first cell of each newly fertilized embryo contained four chromosomes. It received precisely two from the egg and two from the sperm.

  This fitted exactly with the predictions of Mendelism – two sets of paired genes, brought together at the moment of fertilization. Van Beneden’s results have since been confirmed many times over. There are half the chromosomes in eggs and sperm, and the full number of chromosomes are formed when the two fuse to make a fertilized egg. We now know that what is true for sexual reproduction in roundworms is true for all eukaryotic life, including us humans.

  The number of chromosomes varies widely: pea plants have 14 in each cell, we have 46, and the cells of the Atlas blue butterfly have more than 400. Fortunately for van Beneden, the roundworm has just four. If there had been more chromosomes, he could not have easily counted them. By paying close attention to the relatively simple case of the roundworm, van Beneden glimpsed a universal truth about genetic inheritance. Starting with a clearly interpretable experiment with a simple biological system can lead to a wider insight relevant more generally to how life works. For precisely this reason I have spent most of my career investigating the simple and easily studied yeast cells, rather than more complex human cells.

  Putting the discoveries made by Flemming and van Beneden together, it became clear that chromosomes convey genes both between the generations of dividing cells, and also between the generations of whole organisms. Apart from a few specialized exceptions – like red blood cells which, as they mature, lose their entire nucleus and therefore all their genes – every cell in your body contains a copy of your entire complement of genes. Together, those genes play a big role in directing the development of a fully formed body from a lone fertilized egg cell. And across the entire lifespan of each living organism, the genes provide each cell with essential information it needs to build and maintain itself. It follows, therefore, that every time a cell divides, the entire set of genes must be copied and shared equally between the two newly formed cells. This means that cell division is the fundamental example of reproduction in biology.

  The next great challenge for biologists was to understand what genes actually are and how they work. The first big insight came in 1944, when a small group of scientists in New York, led by the microbiologist Oswald Avery, carried out an experiment that identified the substance that genes are made from. Avery and his colleagues were studying bacteria that cause pneumonia. They knew that harmless strains of these bacteria could be transformed into dangerous, virulent forms when they were mixed with remnants of dead cells from a virulent strain. Critically, this change was inheritable; once they became virulent, the bacteria passed that characteristic on to all their descendants. This led Avery to reason that a gene or genes had been passed, as a chemical entity, from the remains of the dead, harmful bacteria to the live, harmless bacteria, changing their nature for ever. He realized that if he could find the part of the dead bacteria responsible for this genetic transformation, he could finally show the world what genes are made of.

  It turned out that it was, in fact, a substance called deoxyribonucleic acid – which you will probably recognize from its more famous acronym DNA – that had the key transformative property. By then, it was widely known that the gene-carrying chromosomes within cells contained DNA, but most biologists thought that DNA was too simple and boring a molecule to be responsible for such a complex phenomenon as heredity. They were wrong.

  Each of your chromosomes has at its core a single, unbroken molecule of DNA. These can be extremely long and each can contain hundreds or even thousands of genes arranged in a chain, one after another. Human chromosome number 2, for example, contains a string of over 1,300 different genes, and if you stretched that piece of DNA out, it would measure m
ore than 8 cm in length. This leads to the extraordinary statistic that, together, the 46 chromosomes in each of your tiny cells would add up to more than two metres of DNA. Through some miracle of packing, it all fits into a cell that measures no more than a few thousandths of a millimetre across. What is more, if you could somehow join together and then stretch out all the DNA coiled up inside your body’s several trillion cells into a single, slender thread, it’d be about 20 billion kilometres long. That’s long enough to stretch from Earth to the sun and back sixty-five times!

  Avery was quite a modest man and didn’t make much of a fanfare about his discovery, while some biologists were critical of his conclusion. But he was right: genes are made of DNA. Once that truth finally sank in, it signalled the birth of a new era for genetics and for biology as a whole. Genes could finally be understood as chemical entities: stable collections of atoms that obeyed the laws of physics and chemistry.

  However, it was the elucidation of the structure of DNA, in 1953, that truly ushered in this brave new era. Most of the important discoveries in biology depend upon the work of many scientists who, over years or decades, have scratched away at the nature of reality to gradually reveal an important truth. But sometimes spectacular insights are achieved much more quickly. So it was with the structure of DNA. In a matter of months, three scientists working in London – Rosalind Franklin, Raymond Gosling and Maurice Wilkins – did the crucial experiments, and then Francis Crick and James Watson, based in Cambridge, interpreted the experimental data and correctly deduced the structure of DNA. Furthermore, they quickly grasped what it meant for life.

  Later, when they were older, I got to know both Crick and Watson quite well. They made a contrasting pair. Francis Crick had a razor-sharp, logically incisive mind. He’d slice problems up until they literally melted under his gaze. James Watson had a brilliant intuition, jumping to conclusions others had not seen, although it was not always clear how he got there. Both were confident and outspoken, and although sometimes critical, they were also highly interactive with young scientists. Together, they were a formidable combination.