Read The Epigenetics Revolution Online
Authors: Nessa Carey
Tags: #Science/Life Sciences/Genetics and Genomics
The Epigenetics Revolution (15 page)
Early programming may also be one of the reasons that it’s been very difficult to identify the environmental effects that lead to some chronic human conditions. If we study pairs of MZ twins who are discordant for a specific phenotype, for example multiple sclerosis, it may be well nigh impossible to identify an environmental cause. It may simply be that one of the pair was exceptionally unlucky in the random epigenetic fluctuations that established certain key patterns of gene expression early in life. Scientists are now mapping the distribution of epigenetic changes in concordant and discordant MZ twins for a number of disorders, to try to identify histone or DNA modifications that correlate with the presence or absence of disease.
Children conceived during famines and mice with yellow coats have each clearly taught us remarkable things about early development, and the importance of epigenetics in this process. Oddly enough, these two disparate groups have one other thing to teach us. At the very beginning of the 19th century, Jean-Baptiste Lamarck published his most famous work,
Philosophie Zoologique
. He hypothesised that acquired characteristics can be transmitted from one generation to the next, and that this drives evolution. As an example, a short-necked giraffe-like animal that elongated its neck by constant stretching would pass on a longer neck to its offspring. This theory has been generally dismissed and in most cases it is simply wrong. But the Dutch Hunger Winter cohort and the yellow mice have shown us that startlingly, the heretical Lamarckian model of inheritance can, just sometimes, be right on the money, as we are about to see.
Philosophie Zoologique
. He hypothesised that acquired characteristics can be transmitted from one generation to the next, and that this drives evolution. As an example, a short-necked giraffe-like animal that elongated its neck by constant stretching would pass on a longer neck to its offspring. This theory has been generally dismissed and in most cases it is simply wrong. But the Dutch Hunger Winter cohort and the yellow mice have shown us that startlingly, the heretical Lamarckian model of inheritance can, just sometimes, be right on the money, as we are about to see.
For I, the Lord your God, am a jealous God, punishing the children for the sins of the fathers to the third and fourth generation of those who hate me
Exodus
, Chapter 20, Verse 5
, Chapter 20, Verse 5
The
Just So
stories published by Rudyard Kipling at the very beginning of the 20th century are an imaginative set of tales about origins. Some of the most famous are those about the phenotypes of animals –
How the Leopard Got his Spots, The Beginning of the Armadillos, How the Camel Got his Hump
. They are written purely as entertaining fantasies but scientifically they hark back to a century earlier and Lamarck’s theory of evolution through the inheritance of acquired characteristics. Kipling’s stories describe how one animal acquired a physical characteristic – the elephant’s long trunk, for example – and the implication is that all the offspring inherited that characteristic, and hence all elephants now have long trunks.
Just So
stories published by Rudyard Kipling at the very beginning of the 20th century are an imaginative set of tales about origins. Some of the most famous are those about the phenotypes of animals –
How the Leopard Got his Spots, The Beginning of the Armadillos, How the Camel Got his Hump
. They are written purely as entertaining fantasies but scientifically they hark back to a century earlier and Lamarck’s theory of evolution through the inheritance of acquired characteristics. Kipling’s stories describe how one animal acquired a physical characteristic – the elephant’s long trunk, for example – and the implication is that all the offspring inherited that characteristic, and hence all elephants now have long trunks.
Kipling was having fun with his stories, whereas Lamarck was trying to develop a scientific theory. Like any good scientist, he tried to collect data relevant to this hypothesis. In one of the most famous examples of this, Lamarck recorded that the sons of blacksmiths (a very physical trade) tended to have larger arm muscles than the sons of weavers (a much less physical occupation). Lamarck interpreted this as the blacksmiths’ sons inheriting the acquired phenotype of large muscles from their fathers.
Our modern interpretation is different. We recognise that a man whose genes tended to endow him with the ability to develop large muscles would be at an advantage in a trade such as blacksmithing. This occupation would attract those who were genetically best suited to it. Our interpretation would also encompass the likelihood that the blacksmith’s sons may have inherited this genetic tendency towards chunky biceps. Finally, we would acknowledge that at the time that Lamarck was writing, children were used routinely as additional members of a family workforce. The children of a blacksmith were more likely than those of a weaver to be performing relatively heavy manual labour from an early age and hence would be likely to develop larger arm muscles as a response to their environment, just as we all do when we pump iron.
It would be a mistake to look back on Lamarck and only mock. We no longer accept most of his ideas scientifically, but we should acknowledge that he was making a genuine attempt to address important questions. Inevitably, and quite rightly, Lamarck has been overshadowed by Charles Darwin, the true colossus of 19th century biology – actually, probably the colossus of biology generally. Darwin’s model of the evolution of species via natural selection has been the single most powerful conceptual framework in biological sciences. Its power became even greater once married to Mendel’s work on inheritance and our molecular understanding of DNA as the raw material of inheritance.
If we wanted to summarise a century and a half of evolutionary theory in one paragraph we might say:
Random variation in genes creates phenotypic variation in individuals. Some individuals will survive better than others in a particular environment, and these individuals are likely to have more offspring. These offspring may inherit the same advantageous genetic variation as their parent, so they too will have increased breeding success. Eventually, over a huge number of generations, separate species will evolve.
The raw material for random variation is mutation of the DNA sequence of the individual; his or her genome. Mutation rates are generally very low, and so it takes a long time for advantageous mutations to develop and to spread through a population. This is especially the case if each mutation only gives an individual a slight advantage over its competitors in a particular environment.
This is where the Lamarckian model of acquired characteristics really falls over, relative to Darwinian models. An acquired change in phenotype would somehow have to ‘feed-back’ onto the DNA script and change it really dramatically, so that the acquired characteristic could be transmitted in the space of just one generation, from parent to child. But there’s very little evidence that this happens, except occasionally in response to chemicals or irradiation which damage DNA (mutagens), causing a change in the actual base-pair sequence. Even these mutagens only affect the genome at a relatively small percentage of base-pairs and in a random pattern, so these still can’t drive inheritance of acquired characteristics in any meaningful way.
The overwhelming body of data argues against Lamarckian inheritance, so there’s very little reason for individual scientists to work on this experimentally. This isn’t surprising. After all, if you are a scientist interested in the Solar System, you could choose to investigate the hypothesis that at least some parts of the Moon are made of cheese. But to do so would mean that you wilfully ignored the large body of evidence already present against this – hardly a rational approach.
There’s also possibly a cultural reason that scientists have shied away from experimental investigations of the inheritance of acquired characteristics. One of the most notorious cases of scientific fraud is that of Paul Kammerer, who worked in Austria in the first half of the 20th century. He claimed that he had demonstrated the inheritance of acquired characteristics in a species called the midwife toad.
Kammerer reported that when he changed the conditions in which the toads bred, they developed ‘useful’ adaptations. These adaptations were structures on their forelimbs called nuptial pads, which were black in colour. Unfortunately, very few of the specimens were retained or stored well, and when a rival scientist examined a specimen he found that India ink had been injected into the pad. Kammerer denied all knowledge of the contamination and killed himself shortly afterwards. This scandal tainted an already controversial field
1
.
1
.
One of the statements in our potted history of evolutionary theory was the following, ‘An acquired change in phenotype would somehow have to ‘feed-back’ onto the DNA script and change it really dramatically so that the acquired characteristic could be transmitted in the space of just one generation, from parent to child.’
It’s certainly hard to imagine how an environmental influence on the cells of an individual could act at a specific gene to change the base-pair sequence. But it’s all too obvious that epigenetic modifications – be these DNA methylation or alterations to the histone proteins – do indeed occur at specific genes in response to the environmental influences on a cell. The response to hormonal signalling that was mentioned in an earlier chapter was an example of this. Typically, a hormone like oestrogen will bind to a receptor on a cell from, for example, the breast. The oestrogen and the receptor stay together and move into the nucleus of the cell. They bind to specific motifs in DNA – A, C, G and T bases in a particular sequence – which are found at the promoters of certain genes. This helps to switch on the genes. When it binds to these motifs, the oestrogen receptor also attracts various epigenetic enzymes. These alter the histone modifications, removing marks that repress gene expression and putting on marks that tend to switch genes on. In this way, the environment, acting via hormones, can change the epigenetic pattern at specific genes.
These epigenetic modifications don’t change the sequence of a gene, but they do alter how the gene is expressed. This is, after all, the whole basis of developmental programming for later disease. We know that epigenetic modifications can be transmitted from a parent cell to a daughter cell, as this is why there are no teeth in your eyeballs. If a similar mechanism transmitted an environmentally-induced epigenetic modification from an individual to their offspring, we would have a mechanism for a sort of Lamarckian inheritance. An epigenetic (as opposed to genetic) change would be passed down from parent to child.
Heresy and the Dutch Hunger Winter
It’s all very well to think about how this could happen, but really we need to know if acquired characteristics can actually be inherited in this way. Not
how
does it happen, but the more basic question of
does
it happen? Remarkably, there appear to be some specific situations where this is indeed taking place. This doesn’t mean that Darwinian/Mendelian models are wrong, it just means that, as always, the world of biology is more complicated than we imagined.
how
does it happen, but the more basic question of
does
it happen? Remarkably, there appear to be some specific situations where this is indeed taking place. This doesn’t mean that Darwinian/Mendelian models are wrong, it just means that, as always, the world of biology is more complicated than we imagined.
The scientific literature on this contains some confusing terminology. Some early papers refer to epigenetic transmission of an acquired trait but don’t seem to have any evidence of DNA methylation changes, or histone alterations. This isn’t sloppiness on the part of the authors. It’s because of the different ways in which the word epigenetics has been used. In the early papers the phrase ‘epigenetic transmission’ refers to inheritance that cannot be explained by genetics. In these cases, the word epigenetic is being used to describe the phenomenon, not the molecular mechanism. To try to keep everything a little clearer, we’ll use the phrase ‘transgenerational inheritance’ to describe the phenomenon of transmission of an acquired characteristic and only use ‘epigenetics’ to describe molecular events.
Some of the strongest evidence for transgenerational inheritance in humans comes from the survivors of the Dutch Hunger Winter. Because the Netherlands has such excellent medical infrastructure, and high standards of patient data collection and retention, it has been possible for epidemiologists to follow the survivors of the period of famine for many years. Significantly, they were able to monitor not just the people who had been alive in the Dutch Hunger Winter, but also their children and their grandchildren.
This monitoring identified an extraordinary effect. As we have already seen, when pregnant women suffered malnutrition during the first three months of the pregnancy, their babies were born with normal weight, but in adulthood were at higher risk of obesity and other disorders. Bizarrely, when women from this set of babies became mothers themselves, their first born child tended to be heavier than in control groups
2
,
3
. This is shown in
Figure 6.1
, where the relative sizes of the babies have been exaggerated for clarity, and where we’ve given the women arbitrary Dutch names.
2
,
3
. This is shown in
Figure 6.1
, where the relative sizes of the babies have been exaggerated for clarity, and where we’ve given the women arbitrary Dutch names.
Figure 6.1
The effects of malnutrition across two generations of children and grandchildren of women who were pregnant during the Dutch Hunger Winter. The timing of the malnutrition in pregnancy was critical for the subsequent effects on body weight.
The effects of malnutrition across two generations of children and grandchildren of women who were pregnant during the Dutch Hunger Winter. The timing of the malnutrition in pregnancy was critical for the subsequent effects on body weight.
The effects on the birth weight of baby Camilla shown at the bottom left are really odd. When Camilla was developing, her mother Basje was presumably healthy. The only period of malnutrition that Basje had suffered was twenty or more years earlier, when she was going through her own first stages of development in the womb. Yet it seems that this has an effect on her own child, even though Camilla was never exposed to a period of malnutrition during early development.
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