Virolution. Frank Ryan

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.’³

      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