What Is Life?

by Paul Nurse

  The real beauty of the DNA double helix they proposed is not the elegance of the gracefully spiralling structure itself. Rather, it is the way the structure explains the two key things that the hereditary material must do to underpin the survival and perpetuation of life. First, DNA must encode the information that cells and whole organisms need to grow, maintain and reproduce themselves. Second, it must be able to replicate itself, precisely and reliably, so that each new cell, and each new organism, can inherit a complete set of genetic instructions.

  DNA’s helical structure, which you can think of as a twisted ladder, explains both of these critical functions. Let’s look at how DNA carries information. The rungs of the ladder are each made from links that form between pairs of chemical molecules called nucleotide bases. These bases come in just four different types, which we can abbreviate from Adenine, Thymine, Guanine and Cytosine, to A, T, G and C. The order in which these four bases appear along each of the two rails, or strands, of the DNA ladder functions as an information-containing code. This is just like the meaning that is communicated by the ordered string of letters that makes up this sentence that you are reading. Each gene is a defined stretch of this DNA code that contains a message for the cell. That message might be the instruction to produce a pigment that will determine the colour of a person’s eyes, make the cells of a pea flower purple, or make a pneumonia bacterium more virulent, for example. The cell obtains these messages from DNA by ‘reading’ this genetic code and putting that information to work.

  Then there’s the need to make accurate copies of DNA, so all the information in the genes can be passed faithfully from one generation of cells or organisms to the next. The shape and chemical properties of the two nucleotide bases that make up each rung of the ladder ensure that the bases can only pair up in a single, precise way. A can only pair with T, and G can only pair with C. This means that if you know the order of bases along one strand of DNA, you immediately know the order of the nucleotide bases on the other strand. It follows, therefore, that if you break the double helix apart into its two strands, each strand can act as a template to recreate a perfect copy of its original partner strand. As soon as Crick and Watson saw that DNA was built this way, they knew that this must be the way that cells copy the DNA making up their chromosomes, and with it their genes.

  Genes exert their major influence on the behaviour of cells, and ultimately whole organisms, by instructing the cell how to construct particular proteins. This information is central to life because proteins are the things that do most of the work in the cell – most of the cell’s enzymes, structures and operational systems are made from proteins. To do this, cells translate between two alphabets: the four-letter alphabet of DNA, made up of the ‘letters’ A, T, G and C; and the more complex alphabet of proteins, which consists of ordered strings of 20 different building blocks called amino acids. By the early 1960s this basic relationship between genes and proteins was understood, but nobody knew how the cell translated information from the language of DNA into the language of proteins.

  This relationship is known as the ‘genetic code’ and it presented biologists with a true cryptographic puzzle. The code was finally cracked during the late 1960s and early 1970s, by a succession of researchers. The ones I knew best were Francis Crick and Sydney Brenner. Sydney was the wittiest and most irreverent scientist that I have ever met. He once interviewed me for a job (which I did not get) during which he described his colleagues by comparing them to the crazed figures in Picasso’s painting Guernica, which hung on the wall of his office. His humour was based on the juxtaposition of the unexpected, and I suspect that was also the source of his immense creativity as a scientist.

  These and other code-crackers showed that the four-letter alphabet of DNA is arranged into three-letter ‘words’ along each strand of the DNA ladder, with most of those short words corresponding to one specific amino acid building block of a protein. The DNA ‘word’ GCT for example, tells the cell to add an amino acid called alanine to a new protein, whereas TGT would call for an amino acid called cysteine. You can think of a gene as being the sequence of DNA words needed to make a specific protein. For example, a human gene with the name beta-globin contains its essential information in 441 DNA ‘letters’ (that is, nucleotide bases), which spell out 147 three-letter DNA ‘words’, which the cell translates into a protein molecule that is 147 amino acids long. In this case, the beta-globin protein helps form the oxygen-carrying pigment called haemoglobin, found in red blood cells, that keeps your body alive and makes your blood look red.

  The ability to understand the genetic code solved a key mystery at the heart of biology. It showed how the static instructions stored in the genes could be turned into the active protein molecules that build and operate living cells. Breaking this code paved the way to today’s world where biologists can readily describe, interpret and modify gene sequences. At the time, this advance seemed so important that some biologists downed their tools, concluding that the most fundamental problems of cell biology and genetics had now been solved. Even Francis Crick decided to shift his focus from cells and genes to the mysteries of human consciousness.

  Today, more than fifty years on, it’s clear that things were not quite done and dusted. Nevertheless, biologists had made dramatic progress. Within a century, the gene – which started as an abstract element – had been radically transformed. By the time I finished my PhD in 1973, the gene was no longer only an idea or a part of a chromosome. It was a string of DNA nucleotide bases, encoding a protein with precise functions in the cell.

  Biologists soon learned how to find out where particular genes lie on chromosomes, to pluck them out and to move them between chromosomes; even inserting them into the chromosomes of different species. In the late 1970s, for example, the chromosomes of E. coli bacteria were re-engineered to contain the human gene that encodes the insulin protein, which regulates blood sugar. These genetically modified, or GM, bacteria produce in affordable abundance a version of the insulin protein that is identical to that made by the human pancreas. They have since helped millions of people around the world manage their diabetes.

  During the 1970s the British biochemist Fred Sanger made another crucial innovation when he devised a way to ‘read’ genetic information. He used an ingenious combination of chemical reactions and physical methods to identify the nature and sequence of all the nucleotide bases that make up a gene (this is called DNA sequencing). The numbers of DNA letters in different genes cover an enormous range, from a couple of hundred bases to many thousands, and the ability to read them and predict the protein they would produce was a great step forward. Fred, who was as extraordinarily modest as he was extraordinarily accomplished, went on to win two Nobel Prizes!

  By the end of the twentieth century, entire genomes – that is, the complete set of genes or genetic material present in a cell or organism – could be sequenced, including our own. All three billion DNA letters of the human genome were first sequenced, more or less completely, by 2003. It was a major step forward for biology and for medicine, and progress has not let up since. Whereas sequencing that first genome took a decade and cost more than two billion pounds, today’s DNA sequencing machines can do the same in a day or two, for just a few hundred pounds.

  The most important thing to come out of the original human genome project was the list of around 22,000 protein-encoding genes, common to all humans, that form the basis of our inheritance. These specify both the features we all share and the inherited characteristics that make us distinct individuals. On its own, that knowledge is not enough to explain what it is to be a human being, but without it our understanding will always be incomplete. It’s a bit like having the list of characters in a play – that list is a necessary starting point, but the next, bigger task is to write the play and find the actors that bring those characters to life.

  The process of cell division has a vital role in linking together the ideas of ‘The Cell’ and ‘The Gene’. Every
time a cell divides, all the genes on all the chromosomes inside that cell must first be copied and then divided equally between the two daughter cells. The copying of the genes and the division of the cell must, therefore, be closely co-ordinated. If they were not, we would end up with cells that would die or malfunction because they lacked the full set of genetic instructions they need. This co-ordination is achieved by the cell cycle, the process that orchestrates the birth of every new cell.

  DNA is copied early in the cell cycle, during a period of DNA synthesis called S-phase, and the separation of the newly copied chromosomes occurs later, during a process called mitosis. This ensures that the two new cells generated at cell division each have complete genomes. These cell cycle events illustrate an important aspect of life: they are all based on chemical reactions, albeit highly complex reactions. On their own these reactions cannot be considered alive. That only starts to happen when all the hundreds of reactions needed to create a new cell work together to form a whole system that performs a specific purpose. That’s what the cell cycle does for the cell: it brings the chemistry of DNA replication to life and in doing so fulfils the purpose of reproducing the cell.

  I began to recognize the fundamental importance of the cell cycle to understanding life during my early twenties, when I was a graduate student at the University of East Anglia in Norwich, searching for a research project to continue my scientific career. I did not think, however, that the research project I initiated in the 1970s would become my research passion for most of my life.

  Like most other processes in the life of cells, the cell cycle is run by genes and the proteins those genes produce. Over the years, my lab’s guiding ambition has been to identify the specific genes that run the cell cycle and then find out how they work. To do this we have used fission yeast (a species of yeast which is used to make beer in East Africa), because although it is relatively simple, its cell cycle is fairly similar to the cell cycles seen in many other living organisms, including much larger, multicellular ones like ourselves. We set out to find strains of yeast that contained mutant forms of genes involved in the cell cycle.

  Geneticists use the word mutant in a particular way. A mutated gene is not necessarily aberrant or broken; it simply means a different variant of a gene. The different plant strains that Mendel crossed, such as those with purple or white flowers, differed from each other because of mutations in a gene that is important for determining flower colour. By exactly the same logic, people with differently coloured eyes can be considered as distinct mutant strains of human being. Often it makes no sense to say which of these different variants should be considered ‘normal’.

  Mutations occur when the DNA sequence of a gene has been altered, rearranged or deleted. This is usually either the result of damage inflicted on the cell – by UV radiation or chemical damage, for example – or due to the occasional mistakes that can occur during the processes of DNA replication and cell division. The cell has sophisticated mechanisms to spot and repair most of these errors, which means that mutations tend to be rather rare. By some estimates, an average of just three small mutations occur each time one of your cells divides: an impressively low error rate of about one per billion DNA letters copied. But once mutations have occurred, they can create different forms of genes that produce altered proteins, which in turn can alter the biology of the cells that inherit them.

  Some mutations provide a source of innovation, by changing the way a gene works, occasionally in a useful way, but in many cases mutations stop a gene from carrying out its proper function. Sometimes, the change of just a single DNA letter can have a big effect. For example, when a child inherits two copies of a particular variant of the beta-globin gene, with a change in a single DNA base, their haemoglobin pigment is not fully effective and they develop a blood disorder called sickle cell disease.

  To understand how fission yeast cells control their cell cycle, I searched for strains of the yeast that were unable to divide properly. If we could find these mutants, I knew we could then identify the genes required for the cell cycle. My lab colleagues and I started out by looking for fission yeast mutants that could not undergo cell division but could still grow. These cells were quite easy to spot under the microscope because they kept growing without ever dividing and therefore became abnormally enlarged. Over the years, in fact over forty years, the lab has identified more than 500 of these large-celled yeast strains, all of which did indeed turn out to contain mutations which inactivated genes required for specific events in the cell cycle. This means that there are at least 500 genes involved in the cell cycle – that’s around 10% of the total set of 5,000 genes found in fission yeast.

  This was progress, because these genes were clearly needed for a yeast cell to complete the cell cycle. However, they did not necessarily control the cell cycle. If you think about the way a car works, there are many components that will stop a car when they break: the wheels, the axles, the chassis and the engine, for instance. These are all important, to be sure, but none of them are used by the driver to control the speed of the car’s travel. Returning to the cell cycle, what we really wanted to find were the accelerator, gearbox and brakes; that is, the genes that control how quickly cells progress through the cell cycle.

  In the event, I stumbled across the first of these cell cycle control genes entirely by accident. I remember vividly the moment in 1974 when I was using a microscope to search laboriously for yet more colonies of abnormally enlarged mutant yeast cells – this was quite a chore because only about 1 in every 10,000 colonies I looked at was of any real interest. It took a whole morning or afternoon to find each of these mutants, and some days I didn’t find any at all. Then I noticed a colony that contained cells which were unusually small. At first I thought they might be bacteria that had contaminated my Petri dish, a fairly common frustration. Looking more carefully, I realized that they could actually represent something more interesting. Perhaps they were yeast mutants that raced through the cell cycle before they had time to grow, and therefore divided at a smaller size?

  This line of thinking turned out to be correct; the mutant cells were indeed altered in a gene that controlled how quickly a cell could undergo mitosis and division, and so complete its cell cycle. This was exactly the kind of gene I was hoping to find. These cells really were a bit like cars with a defective accelerator that makes the car, or in this case the cell cycle, go faster. I called these diminutive strains ‘wee’ mutants, since they were isolated in Edinburgh, and ‘wee’ is the Scottish word for small. I must confess that the wit wears thin after half a century!

  The gene altered in that first wee mutant turned out to work with another even more important gene, one at the very heart of cell cycle control. As things happened, another good dose of happenstance led me to find that second elusive control gene too. I had been working for many months isolating different strains of small-celled wee mutants and had painstakingly gathered nearly 50 of them. This was an even bigger slog than looking for the abnormally large-celled mutants: it took nearly a week to find each one. This challenge was compounded by the fact that most of the strains I laboured to identify were of limited interest because they all contained subtly different mutations of the same gene, which I had by then called wee1.

  Then, one wet Friday afternoon, I spotted another wee mutant. This time my Petri dish was definitely contaminated: the dish, and the abnormally small yeast cells that had caught my eye, were covered by the long tendrils of an invading fungus. I was tired and knew that getting rid of such a contaminating fungus was a long and tedious task. In any case, I assumed this new strain would most likely contain yet another mutant form of the same gene, wee1. I threw the whole Petri dish into the rubbish bin and went home for my tea.

  Later that evening I felt guilty about what I had done. What if this mutant was different from the other 50 wee mutants? By then it was a particularly dark and wet Edinburgh night, but I got back on my bicycle and rode back up the hill to the lab.
Over the next few weeks I managed to isolate the new wee mutant away from the invading fungus. And then – to my sublime pleasure – it turned out that this wasn’t yet another variant of the wee1 gene. It was a completely new gene and, ultimately, the key that unlocked how the cell cycle was controlled.

  I called my new gene cell division cycle 2, or cdc2 for short. Looking back, I sometimes wish I’d given this central part of the cell cycle puzzle a more elegant, or at least a more memorable name! Not least since you’re going to hear rather more about cdc2 later in this book.

  With the benefit of hindsight, all of this was really quite simple, both to do and to think about. Luck was very important too: both the accidental finding of the first wee mutant, which I was not even searching for, and the quirk of fate that meant the ‘failed’ experiment I retrieved from the rubbish bin was the one that eventually led me to the central player in cell cycle control. Simple experiments and thinking can be surprisingly illuminating in science, especially when combined with a good measure of hard graft, hopefulness, and, of course, the occasional lucky break.

  I did most of these experiments when I was a junior scientist, with a young family at home, working in the lab of Professor Murdoch Mitchison in Edinburgh. He provided the space and equipment I needed to do my experiments, as well as an endless supply of advice and comment on what I was doing. Despite all his input, he would not let me include him as an author on any of my papers because he did not think he had contributed enough. It was not true, of course. It is generosity like that which has been my principal experience of doing science, but it gets less attention than it should. Murdoch was an interesting man. Generous, as I have said, somewhat shy, and utterly consumed by his research. He cared little about whether others were interested in what he was doing; he marched to the beat of his own drum. If Murdoch was still around, he might not have approved of my singling him out like this here, but I want to give him full credit for showing me why the best research is both intensely individual and utterly communal.