by Paul Braterman
This short book deserves the widest possible readership. The author, Paul Nurse, shared the 2001 Nobel Prize in Physiology or Medicine for his work on the control of the process of cell division, and is currently Director of the Francis Crick Institute in London, and among other things is Chief Scientific Advisor for the European Commission. Here he gives a marvellously lucid exposition of highly complex subject matter, in a way that makes difficult ideas accessible to non-expert, while I believe that even the expert will gain from the clarity of overall perspective, as well as from the many illustrations of the scientific process in action, drawn from the author’s own career and elsewhere. I do have some criticisms, but will reserve these for later.
I was privileged to hear Sir Paul lecture to Glasgow’s Royal Philosophical Society on the central concepts of biology, and the present book is an exposition and enlargement of the concepts in that lecture. The “five steps” are the cell, genes, evolution, life as chemistry, and life as an information-handling system. After a short but important and highly topical chapter on “Changing the world”, the book concludes with a return to the central question. What is life? What is it about life that gives rise to its wonderful diversity and effectiveness, given that living things are built out of the same atoms as all other material objects, obeying the same laws of physics and chemistry?
The cell is, to use Nurse’s memorable expression, biology’s atom. While generally too small to be seen by the naked eye, it is readily visible under the microscope, and both single celled organisms, and cells as building blocks, were recognised during the 17th century, although it was only in 1839 that it was recognise that all living things consist of cells or assemblages of cells. Cells are defined by their outer wall, which separates them from their environment, but are themselves highly complex and compartmentalised structures, so that each cell is itself a living entity. The vast majority of living things on Earth are single cells, and even cells taken from complex multicellular organisms can be kept alive in the laboratory. Cell division (the formation of two cells from a single parent cell) is fundamental to all life.
Genes are the basic units of inheritance. Their existence was demonstrated in the mid-19th century by Gregor Mendel’s work when he was abbot of the Augustinian monastery in Bruenn (now Brno), where he studied the inherited attributes of peas. In this work he discovered simple mathematical relationships that only made sense in terms of discrete units, which he called “elements”, which we call genes, and which occur in pairs in all cells that have a nucleus. By the 1940s, it was clear that these genes were carried within the nucleus by its chromosomes (the word means “coloured bodies”), and specifically by one particular kind of molecule (deoxyribonucleic acid, or DNA) within those chromosomes. Ordinary cell division is preceded by a doubling the number of chromosomes in the parent cell followed by sharing between its two daughters. However, the kind of cell division that gives rise to germ cells (sperm and ova in animals, and pollen and ovules in plants) takes place without this preliminary doubling. Germ cells therefore contain only a single copy of each gene, so that when these merge in the process of fertilisation, the new generation contains one copy from each of its parents. As for DNA itself, its specific double stranded structure explains its ability to store information, as well as the ability of each strand to act as a template for the other. The DNA molecule is a sequence of four distinct kind of units, which provide a four-letter alphabet that encodes the genetic information. The details will be familiar to many readers, but the way they are described in this book is particularly clear. The DNA copying process is extremely accurate, but not perfect, and the changes that occur during copying are what we call mutations.
Yeasts are the ideal model organisms for studying this process. They are themselves single celled, but resemble the cells in plants and animals in their complexity, and in possessing a cell nucleus. Nurse’s scientific career has centred around how such cells divide, and in particular on mutations that affect cell growth and the division process. This explains why his work has now found applications in the study and treatment of cancers.
Evolution by natural selection, the next major theme of this book, is made possible by mutation. Mutation (of which Darwin was not aware) provides the raw material for natural selection. As Darwin (and, independently, Alfred Russel Wallace) realised,1 natural selection is inevitable given the finite nature of resources, the occurrence of variations, and the tendency of all species to increase their numbers. The resulting competition will lead to what Herbert Spencer called “the survival of the fittest” and the preservation of variants that increase success in having offspring. The existence of this process destroys the basis for Paley’s argument from design, which Darwin himself had at one time found convincing. The ensuing drama of evolution, leading to the enormous diversity of life, is, as Nurse says, “just as full of wonder as any of the creationist myths.” As explained earlier, we know, as Darwin did not, that mutation continually generates new variants, and that sexual production enable such variants to spread through species, while novel combinations are generated by the endless shuffling of genes. Novelty is further enhanced by transfer of genes between different species, for which viruses can act as vectors.
Evolution points towards common ancestry. This in turn implies genetic similarity, especially in those genes controlling fundamental processes, and it turns out from Nurse’s work that one gene of central interest in connection with yeast cell division also turns out to be involved in human cell division, and hence in human cancers.
Evolution-denying creationism implies renouncing huge areas of science, something that many of us tend to think of as a mainly American problem. Nurse’s early experience shows otherwise. Learning about evolution at school, he suggested to his Baptist minister that Genesis was not literally true, but a description of God’s workings, framed in the language of its time. The minister replied that faith in the literal truth of Genesis was essential, Nurse left his church, and so began his transition from religious belief to sceptical agnosticism.
But how do the processes of life actually happen, at the most fundamental level? For this, we need to consider life as chemistry. One of the simplest of chemical reactions carried out by living things, and one of the longest exploited by humanity, is fermentation, the conversion of sugars to other substances, including alcohol, with carbon dioxide as by-product. The book discusses this example, how the reaction is, as Pasteur showed, carried out by yeast cells, and how, even if these cells are disrupted, it can be carried out by catalytically active proteins (enzymes) that they contained. The rest of the chapter takes us through the basic processes of metabolism and energy storage in living cells, including discussion of such subjects as the protein pump, phosphorylation and its role in cell division, and the use of ATP2 as energy store. This is the most demanding chapter in the book, and non-scientists will, I expect, find parts of it very heavy going. Nonetheless, it is full of rewarding and memorable insights. Consider, for example, this explanation of enzyme specificity:
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 3-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.
The fifth step is to consider life as information. Information is essential to biological functioning. The butterfly that entranced the author as a child was receiving and acting on information about its surroundings as it went about seeking food and a mate, and avoiding threats. Living things and their components are the only natural systems that can be discussed in terms of function, and functioning means responding to information about the local environment, from the molecular scale upwards. Information is also required for the construction of living things. As we have seen, it is DNA that stores that information, in the form of its four-letter alphabet. Information management is also involved in gene regulation, which in complex organisms decides in which way a cell will develop. A liver cell, a nerve cell, and a bone-making cell all contain the same DNA, but only certain parts are used in each one of them. Then there is the cellular response to the external environment, as when, in the case of bacteria that can feed on more than one kind of sugar, using different enzymes for each one, the sugars themselves are co-opted into the switching system that turns parts of the DNA on or off, and thus determines which enzymes are made.
Living things can be understood as collections of modules, each of which performs a particular task, connected by feedback loops, and it is the information flow in these loops that determine which modules function at any particular time. However, living organisms are very different in one crucial sense from our own information-handling devices. These are hardwired, but in living things the connections themselves are responsive to circumstances.
We can regard ecosystems in turn as information-handling systems, governing how organisms interact with each other and their wider environment, and we do not know enough about how these work, and sometimes fail. Insect populations are falling around the world, and we simply do not know why this is happening, let alone what the long-term effects will be.
This brings us the next chapter, which is on changing the world. We have done so, to our own great benefit, through medicine, although COVID-19 was already showing when this book was written that our protection from infectious diseases is far from complete. Worldwide, access to medical care is extremely uneven,3 as is the political willingness to pay attention to clinical reality. As Paul Nurse put it a few months ago when writing this book, and as is all too obviously true now,
It is astonishing that politicians in some developed nations should have ignored advice from scientists and experts and have weakened measures to deal with epidemics and pandemics such as these.
We have developed antibiotics, but the inevitable result is that we are breeding resistant bacteria. We have vaccines against what were once dreaded diseases, but an anti-vaccination movement whose activities put themselves and the rest of us at risk. Nonetheless, the main health problems in the developed world are non-infectious diseases and the problems of old age. Cancers in their many forms are one striking example, and here Nurse’s work on cell division four decades ago has turned out to have practical applications. Decoding DNA, including human DNA, is getting easier all the time, and there are a few diseases, such as Huntingdon’s disease, cystic fibrosis, and haemophilia, that have a single genetic cause. Susceptibility to other diseases, including cancers, depend on a whole range of individual genes, but this is something that we can now begin to unravel by collecting DNA from large populations. However, the ability to make such predictions raises its own problems, especially where healthcare is insurance-dependent. And what of other traits involving large numbers of genes, such as intelligence and academic prowess? My own nightmare here is that in future the rich and powerful will have the most opportunity to manipulate the development of their offspring so as enhance the traits that they value most, and that compassion is unlikely to rank highly among these. Such questions lie in the future, but the correct time to start discussing them, Nurse tells us, is now.
Throughout history, advances in biological knowledge have allowed humankind to flourish, from the origins of agriculture to the 20th century’s Green Revolution. But further knowledge will be needed to feed the world’s still-growing population, and as the task of minimising excess CO2 and other forms of environmental degradation becomes ever more urgent. There is great potential for the creative use of our knowledge of genetics, but here progress through controlled genetic modification has been stalled by political opposition. The failure to adopt “yellow rice”, genetically manipulated to produce vitamin a although vitamin a deficiency is a major cause of blindness in poor countries, is one glaring example. Yet fundamentally, all selective breeding of plants or animals is genetic modification.
Within decades, we have the possibility of a new synthetic biology, within which features of different species are combined to produce organisms not attainable through conventional breeding or even piecemeal gene transfer. Such organisms could be of value for using marginal land to grow food, and for drawing down atmospheric carbon dioxide by converting it to biofuels. We also need to consider, as natural ways of sequestering carbon dioxide, the growth and harvesting seaweed and algae. All this will require deeper understanding of interacting ecological systems than we currently possess. And such understanding will require investment in basic research, which as Nurse’s own career shows so clearly, will generate new and as yet unforeseeable applications.
All these matters involve discussion at the political and as well as the scientific level. This does not, however, mean that politics should be used to judge matters of scientific fact. On the contrary. Nurse draws attention to the devastating impact of Communist ideology and Stalin’s intervention on Soviet biology, but I am sure he was also thinking of the impact of free-market ideology and the intervention of Trump (among others) on discussions of global warming science and the science of epidemic control.
In its final chapter, the book addresses the question from which it draws its title, what is life? Nurse quotes the unsatisfactory schoolroom definition, ”movement, respiration, sensitivity, growth, reproduction, excretion, and nutrition”, but as he says this does not really help. Good definitions, in my view, should do two things. They should give us insight into our own thought processes, and draw attention to the most important features of the subject under discussion. The analysis offered in this book succeeds in both these objectives.
The first principle that Nurse draws on is the ability to undergo natural selection. This presupposes a hereditary system that gives rise to variations. His second principle is that a living object must have a physical boundary, such as a cell wall, but that communication across the boundary must be possible. His third principle, which emerges from the features laid down in the opening chapters of the book, is that
… living entities are chemical, physical and informational machines. They construct their own metabolism and use it to maintain themselves, grow and reproduce. These living machines are co-ordinated and regulated by managing information, with the effect that living entities operate as purposeful wholes.The
Life is based on chemistry, and central to life on Earth is the chemistry of the information-storing molecule, DNA. The complexity of life is made possible by the chemical properties of the element carbon, capable of incorporation into complex molecules that are stable, but not too stable to take part in further regulated chemical activity. (I would also mention the chemistry of hydrogen, and in particular its ability to form weak bridges between such molecules. Such bridging is essential to how molecules in living systems recognise each other; for example, in the pairing rules for DNA.)
A good test of any definition is how it deals with marginal cases, and viruses provide one such case. Viruses on their own are inert, but when they invade a suitable host cell they hijack that cell’s metabolism for their own reproduction. So we might be tempted to say that, lacking their own metabolisms, they are not quite alive. Nurse would disagree, for a very interesting reason. All things now alive, with the possible exception of some microbes, depend on intimate association with other living things. We ourselves depend for digestion on a huge population of microbes in our gut, and all complex organisms depend on the functioning of other kinds of organism in their ecosystems. Animals, obviously, rely directly or indirectly on plants for food, while plants in turn rely on bacteria to convert the nitrogen in the atmosphere to more chemically reactive forms, which are needed for the production of proteins and nucleic acids. Moreover, all eukaryotic cells (cells with the distinct nucleus) trace their origins to the ultimate in cooperation, a complete merger between two very different single-celled lifeforms, bacteria and archaea.
All living things rely on DNA as information store, apply the same code (with very minor variations) to access that information for the construction of their working parts, and use ATP for working energy. This clearly indicates a single common origin. But that origin is still unknown. Any solution must resolve a fundamental paradox. Life requires three kinds of component. It requires information storage (accomplished using DNA), working machinery (mainly protein, and built according to specification contained in that DNA), and a boundary between organism and environment, so it is difficult to see how any of these could have come into being unless the others were already in operation. Membranes can form out of relatively simple molecules, and one can imagine them arising from non-biological processes, but that does not solve the problem of the interdependence of the other two components. One attempted resolution of the paradox appeals to the concept of an RNA (ribonucleic acid) world. RNA is chemically very similar to DNA, but slightly easier to synthesise. It is also more flexible, and can form a range of complicated structures that can fold into different shapes and could conceivably act as enzymes. Indeed, some of the most essential and universal enzymes incorporate both protein and RNA. But like DNA, RNA is an information-containing molecule, which sticks to itself according to the same pairing rules, so it could have performed both functions. My own view is that life must indeed have developed from a system in which the same chemical substance provided both the information store and the working machinery, but that RNA itself is far too complex a molecule to have arisen except by a long process of evolution. For this reason I favour the suggestion of my friend and colleague, the late Graham Cairns-Smith, whom Nurse mentions, that the gulf between living and non-living was first bridged by complex minerals such as clays.
Once life came into being, evolutionary processes led to its present variety and complexity, including the complexity of our own brains which, uniquely perhaps among species on Earth, allow us to reflect on our own existence and behaviour.
The more we learn, the more we discover the interconnectedness of life on Earth, with its shared lineage that reaches back into the depths of time. We are unique in our understanding of these things, and also in our power to influence things. The fundamental facts of biology, like, I would add, the fundamental facts of Earth science (compare my review here of Marcia Bjornerud’s Timefulness), combined with our massive power, impose on us what Nurse calls, in the closing words of this book,
… a special responsibility for life on this planet, made up as it is by relatives, some close, some more distant. We need to care about it, we need to care for it. And to do that we need to understand it.
As I said at the outset, this book deserves the widest possible readership. My criticisms stem from this fact. The official price seems high (£9.99; US $20.00 for 40,000 words), and it would have been better if the publishers had gone directly to a mass market paperback. I do not understand why now, of all times, the US scheduled publication date (February 2021) should lag so far behind UK publication in September this year. Some of the material is unavoidably dense, and subheadings (perhaps just the subheadings that Nurse used in his slides at the lecture that I attended) would have been a great help in navigating and rereading. Finally, unaccountably, there is no index. This is particularly serious since important concepts (e.g. S-process, phosphorylation) introduced in an earlier chapter are referred to, as if they were familiar material, much later in the book.
We must hope for a paperback version as soon as possible, in which, I hope, these faults will be rectified.
1] But the ideas of the evolution and mutability of species have a long pedigree, as Darwin himself acknowledged, and the book mentions how the idea of evolution by natural selection was clearly stated by Patrick Matthew in his 1831 publication, On Naval Timber and Arboriculture; see John and Mary Gribbin’s forthcoming On the Origin of Evolution for a fuller discussion.
2] As a chemist, I would pedantically point out that ATP itself is a perfectly stable molecule, although its reaction with water to give ADP and free phosphate is a process that releases energy.
3] The situation in the US is notorious, but while I was writing this review I signed a petition regarding an asylum seeker in the UK who had received a £93,000 hospital bill for treatment after suffering a stroke.