Virolution

‘That’s a complicated subject and one that has been debated at the Natural History Museum at the exhibit on the evolution of man. We use a methodology called Cladistics. It’s basically a phylogenetic analysis [tree of life analysis] of the different lineages of viruses.’

‘This is where you observe them in different species?’

‘Not exactly, no. We’re talking about [analysing sequences over] enormous periods of time here. We have been successful in extracting viruses from our frozen tissue collection and we are having success with extracting DNA from fossil organisms. People have successfully amplified and sequenced DNA from plants that were embedded in Miocene rocks – these are 30-million-year-old plants. So what you can do with this phylogenetic analysis is take a viral sequence from a hantavirus of the Four-Corners deer mouse and compare that to other species of viruses that occur on other branches [of the parallel virus-rodent trees]. From this you can extrapolate what the historical condition was. So we can trace the evolutionary sequence back in time and make comparisons to other lineages that diverged from the lineage you are interested in, much earlier in time.’

The implications were slowly dawning on me. ‘So you see a link between the virus and the mammal that is very close?’

‘That’s right. For example, if we were looking at eutherian mammals [the placental mammals including humans], we might compare the sequences of eutherian viruses to those of the marsupials and egg-laying mammals, which are more ancient.’

‘Because they are similar, but not the same viruses, you raise the question that sometime in the past, just as the animals had a common ancestry, perhaps their viruses might also have had their own common ancestry?’

‘That’s right.’

A surprising idea had entered my mind. From my background knowledge of evolutionary biology, and in particular of evolutionary virology, I could assume that virologists, sharing the same conventional viewpoint as I had up to now, would assume that the viruses, given that they mutate at a vastly faster rate than the mammals, would fast-track their own evolutionary trajectories, to stay close to the evolutionary pathways of their mammalian hosts. But now, thanks to the surprising idea that Terry Yates had planted in my mind, I asked myself the question:

What if both the virus and its mammalian host are influencing one another’s evolution, one evolutionary tree interacting with the other, over the vast time periods of their co-evolution?

I spent a good deal longer than I had initially envisaged with Professor Yates, visiting the Sevilleta and enjoying the courtesy of a stay with him and his family, when I had ample opportunity to examine his work, and to think about his ideas in more detail. When I put my question to Yates himself, he could provide no definite answers other than the observation that viruses and hosts appeared to be following very close co-evolutionary trajectories. Nevertheless, over the months that followed, his explanation of virus-mammalian co-evolution intrigued me deeply and it caused me to look much harder at the relationships between viruses generally and their hosts. In particular I spoke to other biologists, and especially virologists, and I explored the literature far and wide. As far as I could determine, nobody was even thinking along the lines of viruses and hosts influencing each other’s evolution. And thus it would appear that, entirely by chance, I had stumbled across an idea that, if true, would have major implications. It was one of those exciting moments a scientist hopes will come along at some stage of his or her career, a new idea that makes you think long and hard, and even to question some of those ordinary assumptions you have carried with you since your undergraduate years.

What, then, is a virus?

Biologists will differ very widely in their answers to this question. Some will quote the distinguished immunologist and writer, Sir Peter Medawar, Nobel Laureate for his work on tissue transplantation, who caricatured the virus as a piece of bad news wrapped in a protein. But this definition, however whimsical, adds little to any real understanding. Others, usually molecular biologists or geneticists, will adopt a chemical perspective, while Darwinian evolutionists – and until recently symbiologists too – are inclined to see viruses as mere agents of “horizontal gene transfer” between different species. We saw a very interesting example of this with Elysia chlorotica, when the strange retroviruses in the slug’s genome appeared to enable the transfer of key genes “horizontally” across the kingdoms of plants and animals, as represented by the alga and the slug. Another interesting perspective is that of Eckard Wimmer, a professor in the Department of Molecular Genetics and Microbiology at Stony Brook, New York, who became famous in 2002 for reconstructing the polio virus from mail-order components back in his lab.

This experiment provoked a good deal of interest and notoriety. But what Wimmer and his co-workers wanted to do, amongst other things, was to make a conceptual, and perhaps philosophical, point. If you know the genetic formula of a virus, you can reconstruct it. They even quoted an empirical formula for the polio virus, as follows:

C332,652H492,388N98,245O131,196P7,501S2,340

It is strange to think of an organism, even if exceedingly small, being reduced to a list of atoms. One is reminded of the bitter opposition of the gentle French naturalist, Jean-Henri Fabre, the so-called poet of entomology, who, although he greatly respected Darwin as a man and fellow scientist, opposed Darwin’s line of thinking. In Chapter VIII (#litres_trial_promo) of his book, More Hunting Wasps, Fabre described a ‘nasty and seemingly futile’ experiment he had conducted, rearing caterpillar-eating wasps on a ‘skewerful of spiders’. We need not consider the experiment in detail here, only Fabre’s conclusion, which led him to dismiss the concept of evolution through natural selection. In Fabre’s own words, ‘It is assuredly a majestic enterprise, commensurate with man’s immense ambitions, to seek to pour the universe into the mould of a formula … But … in short, I prefer to believe that the theory of evolution is powerless to explain [the wasp’s] diet.’

It is perfectly true that, in certain circumstances, viruses do behave like inert chemicals. Indeed, I once performed a series of experiments that proved this. When I was a medical student at Sheffield University, I was interested in how our mammalian immune system would respond to viral invasion. The penetration of such alien organisms into our bloodstream – literally the very heart of our being – would be a major, and extremely threatening, event. With the help of my mentor, Mike McEntegart, Professor of Microbiology, I set up an experiment in which I injected viruses into the bloodstream of rabbits. Some readers might react with concern about hurting experimental animals, but the virus I used was a bacteriophage, known as ΦX174 – a virus that only attacks bacteria – so the rabbits suffered no illness. Yet their adaptive immune system responded in exactly the way it should to any alien invader, with a build-up of antibodies in two waves, rising to a peak by 21 days, where a single drop of their serum would be seen to inactivate a billion viruses in mere moments.

The point I am making is that this experiment, by its very design, did not really reproduce the living behaviour of viruses. Injecting a virus into such a host was the virological equivalent of landing people, unprotected, on the surface of Mars. The circumstances were unnatural to the virus and it could neither survive nor respond, in the behavioural sense, and so it died. Had I injected smallpox, or influenza, or HIV-1, into people, the result would have been altogether different. The virus would have come alive in its natural host and a fearsome interaction, virus-with-human, would have followed. As this suggests, it is a waste of time, from the definitional perspective, to consider viruses outside of their natural ecology. Outside the host, it could be argued that a virus really does behave much as Professor Wimmer’s formula – as an inert assemblage of genes and proteins. Only in the real circumstances of its life cycle, when it interacts with its natural host, do we witness the real nature of viruses.

This is why, like Terry Yates, I take the view that viruses, in their natural life cycles, should be regarded as life forms. In this sense the extreme reductionism of depicting a virus as a list of chemicals is implicitly absurd. We might similarly contrive a chemical formula for a human being, when we would end up listing a similar collection of atoms, albeit their numbers would be far more gargantuan. People who view viruses only as chemical assemblages miss the vitally important point that viruses have arrived on the scene through a vast, and exceedingly complex, trajectory of evolution, much as we have ourselves. And though Professor Wimmer might seem to be promoting the viewpoint of a virus as inert, this is not his thinking at all. His view of viruses is much the same as my own, and that of the majority of biologists. A virus may appear inert outside its host, but when it enters the host cell, he too regards it as coming alive. And what an extraordinary life form it turns out to be – for here, in the landscape of the host cell, it has the unique ability of taking over and driving the host genome to make it manufacture new viruses.

Here, in the cells of their natural hosts, viruses are born, like all other life forms. Moreover, they can die. When we treat viral illness with viricidal drugs, our purpose is to kill viruses, much as we use bactericidal drugs to kill bacteria. And, perhaps most important of all, the powerful forces of evolution apply to viruses, just as they do to all other life forms. That is why it is so difficult to cure people infected with viruses. If a virus was nothing more than an inert collection of chemicals, there would never have been an AIDS pandemic. The human immune system would have mopped them up from the circulation without any difficulty.

It is clearly important that we take the trouble to understand viruses. We all know that this is important to medicine in combating viral illness in people. It is important also to veterinary medicine in combating diseases in animals, as it is to agriculture in combating diseases in plants. But there is another, even more profound, reason why we should take the trouble to understand viruses. My subsequent researches, and those of virologists such as Luis Villarreal and Marilyn Roossinck, have made it increasingly evident that viruses have played a key role in the evolution of life, from its very beginnings on Earth to the magnificent diversity we see today. Nowhere has the contribution of viruses been more significant than in the evolution of the human species. Perhaps most amazingly of all, this creative role in human evolution and disease has been played by viruses with a very close resemblance to HIV-1.

I realise that these will appear to be startling claims. When I first proposed such novel concepts, they provoked a heady mixture of bafflement and denial. The reaction was hardly surprising since, if I was right, it appeared to threaten the hegemony of the so-called “synthesis theory”, the trilogy of principles that has stood fast for more than seventy years as the theoretical foundation of modern Darwinism.

2 (#ulink_f9d1f72d-94a5-5f9f-ae69-e963c96ca861)

A Crisis in Darwinism (#ulink_f9d1f72d-94a5-5f9f-ae69-e963c96ca861)

What [The Double Helix] conveys … is how uncertain it can be, when a man is in the black cave of unknowing, groping for the counters of the rock and the slope of the floor, listening for the echo of his steps, brushing away false clues as insistent as cobwebs to recognise that something important is taking shape.

HORACE FREELAND JUDSON

A key proposition that has been almost universally misinterpreted among non-scientists as the core of Darwin’s theory is the concept known as the “survival of the fittest”. Nothing could have more alienated religious sensibility, with its potential for misapplication to society, for example its misuse in condoning laissez-faire politics in relation to poverty and hunger, and worst of all its extrapolation to racial and ethnic abuse. It is important, therefore, to clarify the fact that Darwin did not invoke the term. On the contrary, the concept of survival of the fittest was the brainchild of the social philosopher Herbert Spencer, who first proposed it in his book, Principles of Biology, published in 1864.

Spencer had been developing his own thread of thought even before he read Darwin’s Origin of Species, which was published some five years before his own Principles of Biology, but the social philosopher was not educated in biology, and, although his concept was widely seen as synonymous with, or even a clearer exposition of, what Darwin was supposed to have meant by his term “natural selection”, Spencer misunderstood Darwin’s scientifically grounded theory, and he misapplied it as an endorsement of his sociological philosophy. The scientific historians, and philosophers, who have examined Spencer’s ideas have concluded that he saw evolution as a purposeful progression of the physical world, including all biological organisms, the human mind, and human culture and society. Unfortunately it was Spencer’s sociological concept of survival of the fittest, as opposed to Darwin’s scientific concept of natural selection, that led to the inaptly named Social Darwinism of the early nineteenth century, with all of its unfortunate ramifications.

There was never any true scientific foundation to Spencer’s ideas, but since they conveniently fitted with some of the prevailing prejudices of class, and the ethnic and racial bias of the late nineteenth century, extending into the first half of the twentieth century, they became deeply ingrained and influenced political and social belief. It is tragic that Spencer’s ideas still influence a lot of non-scientists today, so that one frequently hears the expression “survival of the fittest” raised in defence or excuse of some prejudicial action. So ingrained did Spencer’s ideas become that, during his lifetime, Darwin himself was put under a lot of pressure, by Spencer and others, to change his basic premise, but, although he briefly flirted with Spencer’s idea, he quickly recovered his senses and returned to his original concept.

Why am I making such a fuss of this when it might be argued that a similar concept of “fitness” is central to Darwinian theory even today? Of course fitness is a core concept to evolutionary biology, but this Darwinian expression is far from the judgemental notion proposed by Spencer. What then did Darwin really imply with his theory of evolution by means of natural selection, and how does the Darwinian concept of “fitness” differ from Spencer’s notion of “the survival of the fittest”?

Admirers of David Attenborough’s Blue Planet series will have observed how, in the warmth of summer, the female Atlantic lobster, a species that can grow up to 20 kilograms in weight, decides that the time has come to lay her eggs. She has already mated – often this happens as soon as she has moulted – but for seven months she has skulked from view in the freezing, deeper waters of the ocean, safe from predators and winter storms and patient in her determination to choose the most opportune moment for her offspring. But now her mind is made up, she is obliged to trudge her month-long marathon to the sandbanks of the warmer, surface waters, where, on her arrival, she must first do battle, claw for claw, with other lobsters to take control of her favoured sheltered pit. Here at last, some eight months after first fertilisation, she deposits her 20,000 or so eggs, which tumble into the pit from grape-like clusters beneath her abdomen, and from which her young emerge within minutes to take advantage of the warmth and limited shelter afforded by their mother’s endurance, discrimination and fortitude in battle. In the case of other marine invertebrate animals, such as sea urchins, and certain species of fish, a single spawning may give rise to millions of eggs. This behaviour, and the very production of vast numbers of potential offspring, is closely linked to what biologists actually mean when they talk about fitness in its true evolutionary meaning.

Fitness, from the Darwinian perspective, is a measure of how successful an individual is in his or her ability to reproduce and thus to contribute to the broad genetic pool of the species. It is a very simple, non-moralistic and non-judge-mental concept, the real emphasis of which is on reproduction. But, as we see with the lobster, this is more complex than merely laying eggs, or, in the case of human beings, bearing young in a womb. The individual has first to survive in the competitive theatre of life and then to compete with others of the same species for reproduction, and further to make possible, even in such limited life histories as that of the lobster, the survival of as many offspring as possible. In fact evolutionary biologists will usually measure comparative fitness of an individual within a species and what they look for is the proportional contribution of an individual’s genes to the species gene pool in a single generation.

Humans do not give birth to millions of eggs at a very early stage of embryological development, but rather to highly developed infants, which demands that they be nurtured for a very long period of time in the womb. For this purpose evolution has designed the human uterus as a single chamber, roughly the shape of an inverted pear, which is optimally designed for bearing a single foetus. The highest recorded number of living offspring born to a human mother in a single pregnancy is the eight babies born to an American mother in January 2009, all of whom lived. They were not conceived in the normal way but through assisted fertility treatment, and it is unlikely that all would have lived without the assistance of modern obstetric care. Indeed, obstetricians rightfully regard any increase above the normal single offspring as carrying an increased risk to both mother and offspring, even for twins.

Fitness, in human terms, is clearly more complex than we see in lobsters, but nevertheless the same basic non-Spencerian considerations apply, in terms of relative fitness.

The modern Darwinian concept of natural selection is brutally simple and depends on a system of probability, amenable to calculus. Where an individual of any species acquires some slight advantage in terms of survival over its fellows, it is more likely to survive long enough to have offspring, and if the advantage is hereditary, the offspring in turn will enjoy the same advantage over their own generation, so the advantage in time becomes part of the evolving species. From the fitness point of view, the hereditary advantage gives the individual, and its offspring at every subsequent stage of reproduction, the chance of making a bigger contribution to the species gene pool than the average member of the species. It’s really that simple. We can see, from the Darwinian standpoint, that relative fitness is a way of measuring advantage from a natural selection point of view. In time, particularly if the affected group within a species is isolated, geographically or otherwise, from the remainder of the species, an accumulation of such hereditary changes – or a rapidly developing major change – will so alter the affected group that they are no longer capable, or likely, to reproduce with members of the original species. This is the perfectly reasonable Darwinian explanation of how new species arise in a linear-with-branching pattern from ancestral species.

The creation of new species from old is termed “speciation”. Spencer, who was influenced by the French evolutionary biologist, Lamarck, believed that evolution was driving all of life, and most particularly the human species, towards a higher, utopian, destiny. But it is clear that Darwin’s theory of evolution by means of natural selection embraces no such ideal. On the contrary, selection works through the biological necessities of survival and comparative success in reproduction, which have nothing to do with morality, and have no in-built drive towards a philosophic, or religious, ideal of individual or societal perfection.

The concept of natural selection, as proposed by Darwin, was both logical and amenable to experimental confirmation, so that, in spite of considerable opposition from both Church and rivals within his own field, it appealed to the majority of scientists, and eventually to the educated society of his day. However, it embodied a weakness of which Darwin himself was well aware. For selection to work, it demanded a source, or sources, of hereditary change, which would give rise to the key advantages in survival, and thus relative fitness, of one individual, or group, over the others of its own species. Today we know that this implies some sort of genetic, or genomic, innovation, but Darwin was hampered by the ignorance of the mechanisms of heredity in his day. The very concept of genetics was unknown and the enlightenment of DNA would be unavailable until almost a century after publication of The Origin of Species. What Darwin achieved, given the science of his day, was, without exaggeration, world-changing. We cannot criticise him if he was obliged to fall back on now-outmoded concepts of parental mixing, or blending, as if the quaint notion of pedigree could somehow supply what we now realise to be the vast genetic and genomic change necessary to give rise to biodiversity. It was an inherent weakness in his theory that was unlikely to go away.

Thus it was not altogether surprising that, at Oxford, in 1894, during his presidential address to the British Association for the Advancement of Science, the Marquis of Salisbury attacked the concept of natural selection. The distinguished Thomas Henry Huxley was in the audience – cast by his critics as Darwin’s bulldog – but in reality one of the most objective, and formidable, biologists of his day. Huxley was faced with the fact that, where many earlier critics had attacked Darwinism from a religious perspective, adopting the Procrustean stance of faith, Salisbury was a highly educated man, an ex-Prime Minister and amateur scientist, and his attack was based in logic. He did not doubt the reality of evolution and he praised Darwin for convincing science, and the more educated levels of society, of this – rather, it was Darwin’s mechanism of evolution, natural selection, on which he focused his criticism. To date no scientist had ever proved in scientific experiment or observation that natural selection could produce a new species from an ancestral one. Moreover, Darwin’s theory assumed a very slow and gradual change in the evolution of life, and biodiversity, implying that the history of the Earth extended, say, to something like a billion years. Meanwhile Lord Kelvin, widely regarded as the foremost physicist in the world, had calculated the presumed age of the Earth from the physics of a cooling body, and pronounced that it could be no more than a million years old – too little time for life’s diversity to have evolved.

Although Huxley defended Darwin as best he could, he was hampered by the prevailing lack of hard evidence, and so inevitably he lost the battle to the scientific methodology of Kelvin. Darwinism had fallen to its lowest point, a nadir that would subsequently be recalled by Huxley’s own grandson, Julian, as “the eclipse of Darwinism”. Indeed, Julian Huxley would go on to describe the pressures on Darwinism that arose about the end of the nineteenth century and extended into the twentieth, when they were compounded by the growing dichotomy of many of the core disciplines of the biological sciences. In a great series of scientific publications, author after author would simply assume that their observations implied evolutionary adaptations, and thus the influence of natural selection, with ‘little contact of [such] evolutionary speculation with the concrete facts of cytology and heredity, or with actual experimentation’. The new generation of selectionists ignored the rising field of genetics, as pioneered by the writings of the Bavarian monk, Gregor Mendel, and they ignored the discovery of mutation by the Dutch botanist, Hugo de Vries. Evolutionary biology fragmented into three different factions – the selectionists, who had an undying conviction in natural selection, Mendelians (what we would now call geneticists), and mutationists, inspired by de Vries – and for several decades the discord continued.

In the opening chapters of his book, Evolution: The Modern Synthesis, Julian Huxley put his finger on the heart of the problem: ‘The really important criticisms have fallen upon Natural Selection as an evolutionary principle and centred round the nature of inheritable variation.’

Today we know that Lord Kelvin was wrong and the Earth is far older even than Darwin conjectured, at roughly 4.6 billion years old, with life beginning at a very early stage in the planetary evolution and thus giving plenty of time for the evolution of biodiversity. Kelvin was ignorant of the radiation at the core of the Earth, which has kept the planet much warmer than would be predicted for an otherwise cooling body. Moreover, Huxley’s book, in its very title, indicates how the raging conflicts of this early phase of evolutionary biology were resolved. It may seem ironic, if perhaps predictable, that they were resolved through a synthesis of the three rival concepts: natural selection, the growing understanding of Mendelian genetics, and the potential of mutation to give rise to the much-needed genetic variation that, when it affected the germ cells, such as the sperm or the ovum, was inevitably hereditary. The consummation of all three forces gave rise to the synthesis theory of modern Darwinism. But this, as Huxley made clear, also implied important differences from the perspective originally adopted by Darwin himself.

Darwin had set out his stall for a slow and gradual change, based on the geological ideas of his hero, Charles Lyell. His vision was of a progressive, implicitly seamless, “transmutation” in living beings through parental blending and selection by nature. But the new evolutionary biology proposed genetic change arising through a series of accidents – copying errors during cell division, when the germ cells, such as the ovum and sperm, were formed. It also recognised the Mendelian nature of genes. Unlike the Victorian assumption, heredity was not a matter of parental blending but depended on discrete units of inheritance – rather like beads of coded knowledge – that were handed down, in what amounted to complementary pairings, one from each of the two parents, as part of the process of sexual reproduction. Only when one brought all three mechanisms into a single, all-embracing synthesis did evolutionary biology make sense.

If the publication of Darwin’s great book was the visionary moment that set the science of evolutionary biology in motion, the synthesis theory, also known as Modern Darwinism or neo-Darwinism, was a key stage in the development and amplification of that vision. It blossomed at the very heart of biology, ramifying through all of its disciplines. With the new, and equally iconoclastic, discovery of the chemical structure and hereditary role of DNA, by Watson and Crick, in 1953, and the revolution in molecular biology and genetics that followed it, Modern Darwinism gained further momentum. But, while not detracting a whit from the importance of these advances, let me draw attention to an obvious implication of the synthesis theory, yet one that is rarely drawn to public attention. Only one of the three mechanisms is based in theory – and this is natural selection. The other two mechanisms, mutation and Mendelian genetics, are fact that can be proven with all of the certainty of modern genetics. Why, in the defence of evolutionary theory against the creationists, have evolutionary biologists not produced these two trump cards out of their sleeves?

In part this omission derives from the fact that mutation has historically been promoted by Darwinians as random, and thus non-creative, while natural selection, usually abbreviated to “selection”, has historically been extolled as the exclusive creative force. This perspective, perhaps understandable three generations ago, is still presented today as the explanation of evolution in the majority of schools, colleges and universities in spite of the fact that there is overwhelming evidence that the reality of evolution is more complex, and decidedly more interesting, than this naïve oversimplification. For the moment I shall put aside the illogical and ultimately misleading historical contingencies so that I can concentrate on the importance of mutation and Mendelian genetics to medicine, where we shall see that they play a fundamental role in our understanding of the genetic basis of many diseases.

Cystic fibrosis is one of the commonest of genetic diseases, affecting roughly one in 2,500 children born in the UK and one in 4,000 of those born in the USA, with a similar incidence in Australia and Canada. Although less common in Asian and African populations – for example, the incidence in US-born Caucasian children is the same as in the UK, while the incidence in Asian Americans is roughly one in 30,000 – the disease is actually global in its distribution, affecting boys and girls with equal frequency. In 1989 an international team of scientists discovered the genetic cause, which proved to be mutations affecting a single gene, known as the cystic fibrosis transmembrane regulator gene, or CFTR, which is located on human chromosome 7, and which codes for the transport of salt and water across membranes in glands that produce mucus and sweat in several different organs of the body. The worst-affected organs are the lungs, the digestive organ known as the pancreas, the liver, intestines, sinuses and the sex organs. Normally the mucus produced by these organs is thin and oily, so that it flows easily and smoothly, but in people affected by cystic fibrosis the mucus is thick and sticky, causing local build-ups and obstructions within the organs. For example, in the lungs this can block the airways, which in turn allows bacteria to invade the stagnant parts of the lungs. This means that sufferers are very susceptible to chest infections, including pneumonia, which threaten health, and even life. Similar stagnation damages the pancreas, which is a major digestive organ. This shows up as failure to thrive in infancy, or as malnutrition through failure to digest food, and particularly fat, in older children and adults. The same genetic malfunction causes excessive amounts of salt to be lost in sweat – this is the basis of the diagnostic test for the condition, known as the “sweat test”. Cystic fibrosis shows a wide range of severity, from the very severe form that manifests at or soon after birth, to mild forms that may be diagnosed in late adolescence or even adult life.

Although there is currently no cure, sufferers can be helped by a number of measures, such as physiotherapy to help keep the lungs clear, and replacement therapies for the defective digestive enzymes. Cystic fibrosis is also one of the frontline illnesses in modern medical research aimed at curing the condition by correcting the genetic cause of the disease. To understand what this means, we need to know a little more about genes and how a malfunction of their normal operation can help in understanding the underlying causes of many important diseases. In fact the basis of genetics is quite simple, and logical, so that anybody can grasp the essential details.

One way of looking at genes is to regard each gene as a very long word written in a code we call DNA. The code itself is made up from an alphabet of just four letters. These letters are chemicals known as nucleotides, containing the nucleic acids guanine, adenine, cytosine and thymine, which are conveniently referred to using the letters G, A, C and T. It might appear a very limited alphabet but if you imagine the many different permutations of just those four letters that are possible in a word that is anything from hundreds to thousands of letters long, you appreciate how the DNA code offers virtually an unlimited variety of words. The 20,000 human genes are grouped together into 46 chromosomes – following the word analogy, the chromosomes might be seen as 46 chapters, which make up the book of our nuclear genome. In the formation of eggs and sperm inside the human ovaries and testes, the gene CFTR must be copied. Each of these germ cells will then contribute a single copy of CFTR to the offspring, so that every baby will be born with one gene from the father and another from the mother.

If, during the copying process, an error is made, so that the spelling of CFTR is defective, the code will be altered. This is what we mean by a mutation. But if you think it through, a mutation such as this will only affect one of the two copies of CFTR. Thus if the baby gets one defective copy and one normal copy, the normal copy might still be enough to prevent disease.

Here we turn to another strand of the synthesis – Mendelian genetics. In Mendel’s day, naturalists assumed that heredity arose through a process of blending of the parental characters, which was adopted by Darwin as the basis for hereditary change in his evolutionary theory. Mendel, the abbot of an Augustinian monastery in Czechoslovakia, happened to be a farmer’s son, and he studied the effects of cross-fertilising different varieties of peas, which he grew in the monastery’s vegetable garden. When, for example, he took the pollen from yellow peas and used it to fertilise the female parts of the flowers of green peas, the offspring were not a yellowish green, as one might have expected if parental characteristics blended. Instead they were all yellow. Even more intriguingly, when Mendel crossbred this new all-yellow generation, the next generation reverted to a mixture of yellow and green, like the original parents. Even stranger still, the ratio of yellow to green in the new generation was not equal: there were three times as many yellow as green peas. By analysing his results, Mendel realised that the inheritance of pea colour could not be based on blending, but rather some discrete factors must be responsible for the two different colours. He had discovered that the coding of heredity comes in small packages, which we inherit from either parents and which we now call genes. But this was not all that Mendel had discovered. What was the meaning of the curious ratios he had observed in the colour experiments?

In fact what he had discovered was that when the offspring inherited two different variations of a gene, sometimes one of the two variations dominated over the other. In the case of the peas, the gene for yellow was dominant. Thus when he blended green and yellow, the offspring, although some only had a single gene for yellow, all appeared yellow. When he further crossbred generations that had one yellow and one green gene, on the law of averages the offspring had a one-in-four chance of having two yellow genes, a two-in-four chance of having one yellow and one green, and a one-in-four chance of having two green genes. Not only does this explain Mendel’s findings, it also proves helpful when we go back to consider the genetics of cystic fibrosis.

Medical geneticists have indeed confirmed that when a child inherits one normal copy of the gene CFTR from one parent and a mutated version of the gene from the other parent, the coding for the normal copy dominates over that of the mutated gene. From the coding perspective, the mutated gene is essentially passive in the presence of the second normal gene. And this, in turn, implies that only if he or she inherits a mutated gene from both parents will a child suffer from cystic fibrosis. In medical genetics, this is known as a recessive pattern of inheritance. From this level of understanding, we see that there are two aspects of the recessive inheritance of cystic fibrosis that make it particularly amenable to gene therapy. The disease is the result of a malfunction of a single gene, CFTR. Moreover, the two defective copies of the CFTR in the sufferer’s chromosomes are passive and can be ignored. All that the sufferer needs to correct the condition is the introduction of a single copy of the normal CFTR gene.