Genes and environment or nature and nurture cannot, as currently portrayed, explain why our genetically identical cells are so different, or the greater-than-expected differences between relatives or twins, or the countless examples of rapidly changing patterns of disease. This brings us to an eighteenth-century scientist called Lamarck and his ideas of ‘soft inheritance’, which we now call epigenetics. Epigenetics could be the missing third element, alongside nature and nurture.
Jean-Baptiste-Pierre-Antoine de Monet, Chevalier de Lamarck, was born in 1744 near Amiens in northern France. Lamarck was a man of many talents. He started first as a soldier in the war against Prussia, then studied medicine, fossils, then finally botany. He worked in difficult conditions at the time of the Great Terror following the French Revolution, when many of his colleagues had been guillotined for saying things that were not politically acceptable. He published his major works during the Napoleonic wars, and 50 years before Darwin he developed an elaborate theory of evolution.1
Lamarck was the first to properly study invertebrate animals, and he was an early champion of the controversial idea that something other than divine intervention was responsible for generational changes in plants and animals. His main theory, formulated in 1809 (the year Darwin was born),2 was that there was a combination of two evolutionary forces. The first was the vague power of complexity, or ‘le pouvoir de la vie’: simple organisms spontaneously emerge and then slowly evolve to become more complex. The second was force of circumstance, ‘l’influence des circonstances’: animal species had adapted rapidly to their surroundings, and formed habits that exercised and improved (or lost) certain characteristics, such as eyes, tails, colours and muscles. But not only did they seem to be able to adapt to their environment, they also passed some of the newly acquired characteristics on to their offspring. This process has since been called the inheritance of acquired characteristics or ‘soft inheritance’.
Like Darwin after him, Lamarck did not use the term gene – the concept was unknown to him and his contemporaries – so he could not explain how these characteristics were passed on. His most quoted example from the many he used is that of giraffes. The tall trees that giraffes ate from, he argued, made them stretch their necks, and the continuous stretching released fluids that made each generation have slightly longer necks. Until recently he and his giraffe neck theory were the butt of many jokes. His observation that plants adapted to different types of soil that they were planted in was more acceptable to his peers – although these possible ‘epigenetic’ effects on plants were seen as too far removed from ‘divinely created’ humans to be taken seriously.
Lamarck’s theory of evolution was heavily criticised in France by his peers and was soon forgotten. Unlike Darwin, who after a long struggle with creationists ended up triumphantly buried in a prestigious plot in Westminster Abbey, Lamarck finished his life blind and penniless, dumped into an unmarked limepit somewhere in northern France.3 Even after his death, his French colleagues continued to demean and ridicule him, notably in the so-called ‘eulogy’ given by his rival George Cuvier in Paris a few years later. History likes winners and losers, and many a schoolchild since then has learned of the foolish Lamarckian theories, trumped by the brilliant and logical Charles Darwin. But the reality was not so simple. Darwin was actually an admirer of Lamarck, and his works contain several references to the notion that inheritance of acquired characteristics might be an alternative or parallel method of evolution, albeit more minor. But at the time most of the scientific world was more interested in our descent from apes and did not listen.
The work of the unfortunate Chevalier de Lamarck was not the only precursor of modern epigenetics. Paul Kammerer was a Viennese musician turned biologist who in the 1920s had a fascination with amphibians and with Lamarck’s ideas. He was a busy man who like many men of his day performed experiments in diverse areas. His own – and from today’s perspective rather eccentric – theories of life were often quoted by Freud and others. Kammerer claimed (without formal proof) that he had skilfully manipulated and bred cave-dwelling salamanders (olms) with no eyes to be able to see. He raised salamanders in very different breeding environments and apparently altered their offspring’s breeding patterns.
He was most famous for claiming to have made midwife toads breed in the water as opposed to on land, just by raising water temperatures. The midwife toad gets its name because the male carries the fertilised eggs around on its hind legs. He also reported that his new generation of toads were now exhibiting black nuptial pads on their feet with tiny spines to stop them slipping during mating in water, just like their distant ancestors.
Kammerer drew big audiences for his international speaking tours, which made him good money. The New York Times in 1923 hailed him as the new Darwin, having proven Lamarck’s ideas of inherited acquired characteristics.4 He even had a celebrity mistress, Alma Mahler, the newly widowed spouse of the late Gustav Mahler. Alma Mahler was the femme fatale of her time, who while picking her way through famous musicians and artists, also worked as Kammerer’s assistant. She complained about his sloppy record-keeping and over-eagerness for positive results. Kammerer soon became known in Vienna as the ‘Wizard of Lizards’, as much for his wild social life and strong socialist and pacifist views as for his science. He had also irritated some Americans both from his hyped success in the media and because when he visited America during Prohibition he predicted piously that future generations would benefit from the alcohol-free environment of their parents.
But Kammerer’s fame was not to last. Scandal hit when in 1926 the journal Nature published a letter stating that the famous toad experiment had been faked. G. K. Noble, Curator of Reptiles at the American Museum of Natural History, had visited his old lab in Vienna unannounced when Kammerer was still on his money-making world lecture tour and inspected the famous specimen of the preserved but long-dead toad. The black pads, Noble claimed, had a far more mundane explanation: ‘it had simply been injected there with Indian ink’.5 Six weeks later Kammerer shot himself in the forest of Schneeberg, leaving a suicide note with a somewhat ambiguous content. ‘Who besides myself had any interest in perpetrating such falsifications can only be very dimly suspected,’ he wrote. This note was also, strangely, published in Science – an unorthodox posthumous way of improving your CV.6
Interest in Kammerer’s experiments revived 40 years later in 1971 with the publication of a book on the incident by the Hungarian author Arthur Koestler. In The Case of the Midwife Toad he suggested that the toad experiments might have been doctored by an early Nazi sympathiser (a so-called Hakenkreuzer, swastika-lover) at the University of Vienna where political activism was rife.7 Koestler also pointed out that the dodgy toad had been exhibited earlier in 1923 in Cambridge to known sceptics who had examined the specimens and hadn’t spotted the crude ink injections and claimed to have seen the spines. This suggested that the ink could have been added later.
In 2009 a Chilean biologist, Alexander Vargas, reignited the debate by elevating the vilified Kammerer to the status of the real father of epigenetics and Lamarckian biology. He examined Kammerer’s lab books and breeding experiments, and concluded that many of his findings that were ridiculed in the past could now be supported by modern science and our understanding of so-called imprinted genes.8 Not everyone agreed. A subsequent editorial and some detective work in an American biology journal in 2010 showed evidence that he had a track record prior to the toad incident.9 He had previously tried to artificially touch up an image of a salamander’s spots while submitting an article for the same journal. They damned him a second time as a fraud and a bad example to others. However, they also admitted that even today, up to 25 per cent of scientific images submitted to journals have some degree of ‘enhancement’. So whether the Wizard of Lizards was just a confident fraudster or a genius who was the first to show Lamarckian inheritance, as well as a victim of jealous Americans and Nazi saboteurs, will never be known for sure.
Two years later in 1928 another remarkable, if unpleasant, scientific character emerged from Stalin’s Russia. Trofim Lysenko may have unwittingly cost Russia the Cold War 50 years later. He was a Ukrainian self-taught biologist of peasant stock who embraced neo-Lamarckism. Like Stalin, he disliked the Western- and then Fascist Germany-dominated world of traditional genetics run by elite intellectuals.10 Their ideas of genetic determinism, eugenics and the power of heredity ran against socialist ideals, which rejected inherited privilege.
Lysenko first came to Stalin’s notice by performing an amazing farm experiment. This happened during the new collectivisation policy of changing small family-run farms into state cooperatives. Local Soviet methods to improve agricultural output were given top priority as part of the new five-year plan. Lysenko took one large farm’s entire seed supply (without their approval), wetted the seeds and buried them in sacks in the frozen ground to ‘prime’ them for the next year’s harvest, so that they and their progeny would be tougher and produce more wheat. The results were spectacular and more experiments were started immediately, slightly altering the conditions of the priming, or vernalisation, as it was known. Stalin loved the simplicity of his approach, and its PR spinoffs, as all peasants could now become barefoot scientists as well as farmers.
With no need to rely on the infrastructure provided by universities, and on complex and expensive lengthy plant-breeding experiments, Lysenko offered immediate solutions to Stalin and rapidly gained power and influence, becoming head of Soviet biology. He entertained visits from prominent US and European scientists eager to understand his vernalisation methods. But there was a dark side. Anyone who challenged his unorthodox methods or results, or openly supported Mendel or Darwin, was viewed as a traitor to the revolution and either shot or sent on permanent sabbatical to the Gulags. In 1948 genetics was officially banned; it was called a ‘bourgeois pseudoscience’ until 1964.
There was, however, one little problem with the Lysenko alternative of Lamarckism. It was all one big lie. None of his experiments ever succeeded. No crop yields increased, no trees grew. Failures were covered up, although the rolling programme continued to obscure the truth. Millions of Russian peasants died of starvation, and because of the long-term lack of scientists and plant-breeding innovations, postwar Soviet Russia embarrassingly ended up dependent on America for its food imports. The USA had meanwhile successfully bred maize hybrids using traditional Mendelian genetics and were now tripling their yields. The collapse of the Soviet empire was not due to its failures in arms or technology, but ultimately to failures in agricultural genetics and biology.
But the man who, in retrospect, can be regarded as the real father of modern epigenetics was Conrad Waddington, an Englishman born in India in 1905, who was way ahead of his time. He too started in science with a strange interest in amphibians and how they developed – though he wisely stayed clear of toads. He moved on to study genes and heredity in fruit flies. He was, just before the Second World War, the first to suggest and use the term epigenetics, derived from the Greek prefix epi-, above or around, and genetics. He was fascinated in early development of the fetus and interested in the mystery of how cells can start so simply and then develop specialised functions, yet all have the same genetic material.
Before the structure of DNA was discovered, Waddington believed that tiny changes (mutations) around our genes could lead to differences in the way that cells and whole animals develop and could in theory be passed down generations. As a Fellow of the Royal Society, he was one of the most eminent pre-molecular developmental biologists of his time and his work suggested that some of what Lamarck had said might just be correct.11 Unfortunately, following the stir caused by the elucidation of DNA structure and the molecular biology of genes, his work was overshadowed and forgotten for many years.
Looked at from today’s perspective, how does Waddington’s or indeed Lamarck’s theory hold up?12
While Lamarck made some very interesting and relevant observations, he should perhaps have steered clear of talking about both giraffes and lettuce in the same breath. Plants and animals differ in quite a few ways. One difference is that plant cells are pluripotent (multipurpose): they can all change to another form if needed and become specialised. In this way small cuttings can sprout a whole new plant – unlike someone attempting to plant a human finger. This means that they must have ways of modifying the genetic information from the identical DNA contained in each cell to provide the message to make a specialised daughter cell. Epigenetic mechanisms were supposed to play a part in this, but after the cells divide, these new signals were believed to be wiped clean again, so that the cell could remain pluripotent. This would mean that cells had no remnants of interfering messages – for example trying to make cells become leaves or roots. The idea that all memories of how a cell had diversified were completely wiped clean as the pollen (sperm) and the egg (called gametes) were formed to make a new generation has been central to the traditional view of genetics. We now know this isn’t exactly true. The wiping process isn’t perfect.
Over ten years ago a group in Norwich discovered a natural case of epigenetic changes in plants. Remember this means a heritable effect that is not due to changes in DNA structure. A ‘mutant’ version of the common toadflax plant, a pretty yellow wildflower growing in hedgerows, results in flowers with radial petals (five), rather than the normal two.13 What was unusual was that although the DNA structure was the same in both plants, the ‘mutation’ could still be passed on. Normally a mutation is a change in the actual DNA – which was not the case here. The researchers found this change was due to something called ‘methylation’, which is a key part of epigenetics in animals as well as plants, and one that we will return to later. In the mutant plant, a key gene (called Lcyc) is extensively methylated and in the normal plant it is not.
What methylation means is that at certain sites (usually cytosine bases) of the gene’s DNA, small chemical methyl groups (Me) floating around the cell attach themselves to it, rather like sticking an olive on a cucumber with a cocktail stick. This has the effect of stopping the gene producing a protein. We call this inactivating it or ‘switching off’, and we know that in most cases methylation stops a gene from working, or ‘being expressed’, while reversing the process (un-methylating) usually switches the gene back on. By being turned on we mean that it is expressed and more protein is produced. While this process, unlike a mutation, is reversible, it can also last a long time.
The two main epigenetic mechanisms
The Norwich team found that most subsequent generations of toadflax plants had the same radial petal pattern, and carried the same deactivated gene due to methylation. This showed that the information couldn’t have been wiped and reset as previously believed. This was the first clear modern evidence that natural epigenetics occurs and can be passed on across generations. Others were soon to follow.
How do plants know when to flower? It seems a simple question, but until recently we had no idea of the answer. The arabidopsis plant (thale cress) alters the timing of its flowering by epigenetics.14 In response to prolonged cold (as in winter), the Flowering Locus C gene which normally prevents flowering is methylated and deactivated, allowing this variety to flower in the spring. The trait is then passed on to the next generation, even if there is no cold winter. Ironically this experiment showed that the vernalisation mechanism favoured – and faked – by Lysenko was actually a real biological phenomenon.15 If he had actually tried to do proper experiments, and politics and science hadn’t clashed, he might have produced valid results.
Plants are one thing, but animals are obviously more relevant to us. Although we share around 40 per cent of our genes with the banana, we share more genes and genetic mechanisms with other animals. So can genes also be modified in animals, and can they indeed be passed on to the next generation as Kammerer described for the foot pads of toads?
The water flea (Daphnia) is a tiny aquatic species that as adults have a variety of defences against predators. These include helmets and spiny tails. Some fleas have both, some have one, and some cool fleas none at all. What is strange is that these fleas have identical DNA – like identical twins.16 Place a young flea in water with no trace or odours of predators and they will develop no defences. But if you put its genetic clone in another tank with old traces of a nasty fish, it will develop a spine and helmet. Put the babies of these two in opposite environments, and they will be armed according to the environment of the mum rather than their current aquarium. Just as intriguing is the fact that this effect lasts a few generations and fades.
Caterpillars and butterflies look and behave very differently but they have exactly the same DNA structure. Their cells have developed differently, and these differences must therefore be epigenetic. Butterflies have also been found to show very different mating tendencies if the temperature on the day they were born varies by just a few degrees. Female squinting bush brown butterflies who developed as caterpillars in cooler temperatures (17°C) were more likely to have flashy wings and be chasing males than their genetically identical twins brought up at 27°C, who behaved more demurely.17
We don’t normally give much thought to the billions of chickens bred each year, unless it’s to how we like them cooked. But they can be very useful for research. Chickens make ideal adoption experiments, as their eggs can be nurtured and hatched and the chick reared with no contact from either parent or social workers. In one experiment parent chickens from the same genetic stock were raised in one of two scenarios: one was a comfortable private clinic-style environment of 12 hours of daylight then 12 hours of night (called a predictable light rhythm) in which they could eat in a relaxed way. The other was a Guantanamo Bay-style scenario where they had sadistic unpredictable light rhythms which, as they only eat in daylight, meant they had unpredictable eating opportunities that could be halted at any moment.
The researchers then looked at the eating patterns of the offspring of both groups when they were now all raised uniformly in the comfortable regular daylight and eating lifestyle. Those chicks from parents raised in the Guantanamo Bay-style who had never met either of their parents had a more efficient and aggressive eating behaviour than their genetically identical but parentally privileged coop mates, who were more relaxed and preferred to look around for more tasty worms who often got away. The efficient policy worked and the Guantanamo chickens got fatter. The researchers saw epigenetic changes in the offspring and suggested these had affected immune and hormonal genes such as oestrogen.18 This suggested how epigenetics could provide survival advantages. Environmental stresses could prime future generations to be able to cope better in the same situations – a brilliantly effective form of short-term evolution.
So what about animals that are more similar to us than butterflies and chickens? Mammals like mice share around 90 per cent of their genes with us, including most of the known disease genes. A remarkable experiment by Randy Jirtle at Duke University19 has shown that simply by slightly altering the diet of a certain type of pregnant mouse (called Agouti mice) you can change their offspring from chubby blondes to skinny brunettes; and moreover that this effect of grandma mouse’s diet can be passed on for three or more generations until it fades. The Agouti gene normally produces a yellow fur pigment, but if it is switched off by methylation-inducing chemicals in food, it produces a brown pigment. This reversible inherited change, which does not alter the DNA structure, is the essence of epigenetics.
Until recently it was thought that these epigenetic findings were just in a few rare or exceptional genes – so-called imprinted genes – which are much more common in mice than man. Remember we inherit two copies (alleles) of every gene: one from each parent. In most animals a major battle goes on between the genes of the usually absent father and those of the mother. The father’s genes are trying to increase the size of the fetus – so that it has a greater chance of survival – at the expense of the mother,20 who is trying to conserve her resources and live long enough to have more children. In mice, the mother usually wins: in several hundred genes she manages to permanently suppress the father’s copy of the gene by this imprinting mechanism and so keep the fetus a manageable size. Humans have around 50 of these imprinted genes, which form the battleground of parental gene warfare and have a major role in the size and development of the fetus. While these 50 genes are important,21 we know now that the rest of our 25,000 genes can also be influenced epigenetically.
These recent exciting findings in animals have confirmed work and ideas dating back to Lamarck, suggesting there is more to the inheritance of genes than just the painfully slow process of Darwinian evolution and natural selection. Soft inheritance is the parallel faster route by which we human beings adapt to our surroundings, and also explains many of the emerging ideas of how we are moulded into individuals.
But before we get into the extraordinary implications of this new understanding of soft inheritance, it is worth considering how our attitudes to traditional inheritance have altered over the last 50 years.
‘Happiness gene discovered’ leads the headline from the UK Daily Telegraph in May 2011.22 ‘Those with two sets of the gene – one from each parent – are almost twice as likely to say they are satisfied with life, compared to those who lack a copy’. We are now becoming blasé hearing about these stories over our daily cornflakes or muesli: the media have to sex them up to grab our attention. Nearly every disease or behaviour studied has shown some influence of our genes – and most human studies involve twins. Many of these twin studies have totally changed our perceptions of diseases. These include ‘boring’ wear-and-tear diseases of old people such as arthritis of the knees, back pain, cataracts of the eyes,23 varicose veins or even haemorrhoids.24 All of these turned out to have surprising major genetic influences.
Other real breakthroughs have been achieved in areas of personality and behaviour such as autism and schizophrenia, where gene discoveries have shifted perception of guilt. Now we accept the involvement of neurochemicals and genes in the brain, rather than just bad parenting and dangerous vaccinations. Genetic influence has been competing with a strong and long-standing Christian culture of believing that sin causes sickness – particularly when the sickness is mysterious or affects the brain. The popular acceptance of twin studies and genetic influence on our personalities and traits has waxed and waned since the 1920s, when the first proper twin studies were started in Germany and the USA.25 Until the 1950s most people seemed happy to believe in some degree of genetic determinism, and then in the 1960s and 1970s came an environmentalist backlash, often linked to socialist ideals in education and equal opportunities. This look at history reminds us that our views and interpretation of biology and science are just as influenced today by social, religious and political pressures as they were in the careers of Lamarck, Darwin or even Lysenko. We often still believe what we want to or think we ought to believe.
Early twin studies in the 1960s were heavily criticised, usually by social scientists philosophically opposed to the notion of genetic influence on personality and IQ. They said that parents might be more likely to treat identical twin pairs more similarly than would parents of fraternal or non-identical twins. Although difficult to prove conclusively one way or another, there is no clear evidence of a bias by parents. More important, even if there were, its effect would be trivial and would only change heritability estimates by a few per cent.26 Some of these scattergun attacks in the pro-environment culture of 40 years ago did however eventually hit home, casting doubt on some of the genetic findings.27
As a bonus, critics gleefully suggested that some twin researchers were fraudulent. An eminent British educational psychologist, Sir Cyril Burt, produced papers showing that IQ was strongly heritable. He was an honorary president of Mensa, had been a member of the Eugenics Society, and helped start the 11-plus exam in schools – none of which were popular in the 1960s and 70s. When he died in 1971 one of his neo-Marxist critics, Leon Kamin, a member of the group Psychologists for Social Action and a junior academic in rat psychology, began his campaign. He found that Burt’s original research records and notes had been destroyed. He was suspicious and dug some more, culminating in claims of fraud in a book that was later publicised in 1976 by the journalist Oliver Gillie in the Sunday Times.28 By comparing his published papers they found that Burt unerringly produced the same precise estimates of similarity, even when the numbers of twins in his studies subsequently increased. Although possible, repeating statistics so exactly in science is unlikely. They also accused him of inventing non-existent co-authors. Burt, being dead, could not defend himself, although it turned out years later that the co-authors probably did exist and, with a witch hunt going on, were keeping their heads down. Burt was branded a fraud and the environmentalists used this to condemn all twin and genetic findings.29 Indeed Kamin, whose career then took off, went so far as to claim that IQ had zero heritability. The power of the environment was briefly supreme again, and genetics squashed for nearly another two decades.
Ironically, Burt’s estimates of IQ heritability of 60–80 per cent have since been replicated multiple times in over 10,000 subjects in twin, adoption and family studies, and the idea that he was falsely accused has gained momentum since the late 1980s.30 There is an interesting historical parallel with allegations of fraud against other eminent scientists, not only Kammerer. Isaac Newton has been accused of rounding up his speed-of-sound calculations and of plagiarism about his gravity theory. In the genetics field, the famous monk Gregor Mendel was the first to describe the concept of heredity and dominant and recessive genes. When counting his peas he managed to round the numbers up very neatly so that they met the expected ratios exactly. But as his theory, like Newton’s, proved to be correct, he got away with it.31 The environmentalist critics of Burt and genetics were vociferous and persistent but were never able to show that twin studies were wrong, just that they had possible flaws.
One of the reasons I started to study twins and set up the UK Twin Registry in 1992 is ironically thanks to the same pro-environment lobby that destroyed Burt. In the 1970s and 80s in the UK the grant bodies and academics in psychology and sociology were firmly in the pro-environment camp with its dogma that all humans were created equal and that genetic research on IQ was akin to racism. Because of the pressure from the socio-environmental lobby, twin funding dried up for the UK academics. Believing they couldn’t beat the tide, they and their gifted teams sensibly left for well funded posts in the US and Australia. This left no large-scale twin research in the UK, where most of the methods since Galton had been invented. In 1992 I was lucky to find the tide beginning to turn. The media and some grant bodies were now generally helpful, and importantly there were thousands of willing volunteer twins keen to help research without a political agenda.
Irritatingly for the environmentalists, although they rightly claimed that some of the anecdotes were exaggerated, they couldn’t explain away the overall data of identical twins raised apart. Tom Bouchard and his colleagues in Minnesota in the 1980s had slowly built up an impressive collection.32 As well as confirming the heritability results from the larger twin studies for diseases like diabetes and obesity, they confirmed an IQ heritability of 70 per cent – similar to Cyril Burt’s findings. Their novel observations into our behavioural traits and personality raised many new questions about the nature of our identity and even free will.
In my office at work is a giant poster of hundreds of photos of twin faces that I look at every day. As they pose for the camera, strikingly, all pairs have the same look. Some glum, some shy, some smiley – but all the same. From my interviews with the many twins in this book and over the last twenty years, it has become clear that identical twins, whether raised together or reared apart in humdrum or crazy families, tend to look alike, talk alike and have very similar mannerisms and facial expressions. These are traits which as humans we are extra-sensitive to picking up. These particular traits appear pretty much hard-wired, as I’ve yet to see any exceptions. However, from examples I use later it is clear that under the surface veneer, fundamental differences often emerge in terms of behaviour and disease.
Changes in behaviour, for example, are driven by changes in our brain – in the billions of brain cells that communicate constantly with each other via trillions of electrical neuronal connections that control all our thoughts and actions. But each nerve cell, which is itself a very complex machine, is driven by exactly the same structural DNA to function via its proteins. These should be exactly the same in each cell in the body and the same in identical twins. But we know that differences do occur, so something must happen to the DNA to make it act differently to produce different chemical and electrical signals that alter our behaviour. Let us start to dissect ourselves and our brains in depth by first taking a look at a unique human trait: happiness.