Why is there so much talk about epigenetics?

Ottawa, the capital of Canada,  greets each Spring with a festival featuring a million blooming tulips. That May festival got its start in 1953, and was the result of a gift from the Royal family of Holland, a gift given in recognition of two important events linking Holland and Canada during World War II. The Dutch Royal family had taken refuge in Ottawa, and Princess Margriet was born there in 1943. The other significant event was the liberation of western Holland, including the cities of Amsterdam, Rotterdam, and The Hague, by Canadian soldiers, for which the people there remain grateful to this day. When the War ended in 1945, the Dutch Royal family sent 100,000 tulip bulbs to Ottawa, and each year they renew the gift.

The liberation of western Holland was particularly critical, because by April of 1945 the people living there had been subjected to starvation so severe that thousands died (estimates centre around 20,000 dead, with the health of many more people seriously affected). In retaliation for civilian resistance, the German army had put an embargo on food shipments to the area in the Fall of 1944. Although they allowed delivery by water after November, that avenue was closed by the unusually harsh winter conditions, which froze the canals. The fighting made transportation by airdrop difficult. The 4.5 million citizens of that part of the country could only get an average of 1,000 Calories of food a day by the end of November, 1944, and by the end of February that amount had dwindled to 580 Calories (the average consumption today in North America is about 2,500 Calories a day).

The starvation conditions of the winter of 1944-45 is referred to by the Dutch as the “Hongerwinter”. One of the outcomes of that period was that babies born during the starvation were smaller than average, which is not surprising considering the nutritional states of their mothers. Epidemiological studies have demonstrated subsequent health problems of this birth cohort, again, not surprising given what we know about low birth weight. But some later studies also found that the children of these children, who were born during nutritionally prosperous times, also had health problems. The proposed explanation for this “knock-on” effect is “transgenerational epigenetic change”, which means, changes to the inherited genome due not to alterations in DNA, but to other kinds of chemical changes in the genome. Supposedly in the case of the Dutch children, there were non-DNA changes to the original hungry mothers’ chromosomes that led not only to their children’s subsequent health problems, but also to health issues of their grandchildren. This is human epigenetics reaching across generations, and it is a radical idea, for reasons I will explain. It is also hotly debated. Before considering “transgenerational epigenetic change”, it’s useful to focus on epigenetics itself. An interesting topic.

What is epigenetics?

Epigenetics refers to differences in the chromosomal material that are not due to changes in the sequence of DNA bases, or mutations (although mutations can influence epigenetics). One form of epigenetics is due to the way the chromosomes are made compact in the cell. The DNA of the average human chromosome is about 6 centimeters (just under 2.5 inches) long if it were stretched out, which it certainly isn’t, because cells aren’t nearly that far across; an average liver cell nucleus is less than one-thousandth of a centimeter in diameter. To pack the average chromosome into its nucleus requires making it more compact by about 5- to 10,000-fold. The ratio between the total length of a chromosome and the nuclear diameter is about the same as the ratio between this dash, —, and the total length of this essay.

DNA compaction is one of the most awesome (yes, that’s the right word) features of biology, and is still a subject of intense study. The DNA chain itself is wound around clusters of small basic proteins called histones. If the compaction stopped there and we had electron microscopic eyes, the chromosome would look like beads on a string, with its overall length reduced by about 7 times. A thousand times greater compacting is still needed to get the chromosome into a cell. This necklace now folds back and forth on itself over most of its length, reducing the overall length by several times. That folded structure then folds into a higher-order loop, which in turn assembles itself on a protein scaffold. This series of foldings and windings results in the awesomely compact chromosomal structure.

chromosome_compaction
An outline of chromosome compaction. The DNA double helix (far left) is wound around a protein structure made of histones (the nucleosome), and then a series of foldings produces the required compression seen in the chromosome itself (far right).

This densely packed chromatin is not accessible for genetic readout, and is part of one epigenetic mechanism in cells. In general, the tight packing needs to be modified, loosened, which involves enzymatic reactions that change the chromatin in specific parts of the genome and open it up for genetic expression.

Another form of epigenetic regulation of genes is due to a chemical modification of one of the DNA bases, cytosine, by adding a methyl group (—CH3) to it. This chemical decoration influences whether nearby genetic material can, or will be, expressed. A high density of methyl-Cytosine groups near a gene in DNA can cause it to be silenced. And there is yet a third epigenetic mechanism now in view, which is gene regulation by small RNA molecules that bind to, and silence, specific parts of the chromosome. None of these epigenetic changes involve altering the sequence of DNA; that’s what epigenetic means. But they can be handed down between mother and daughter cells, and they often are. This is critically important for all forms of multicellular biology, like the human body.

Epigenetics and your left thumb

First of all, if you haven’t done this before, a thought experiment. The DNA of a complex organism such as a toad or a human is almost exactly identical in sequence in each of its cells, and in both toads and humans it is a composite of chromosomal contributions from mom and dad. Then how is it that we have skin cells, and neurons (of many different types), and left thumbs? What makes a skin cell a skin cell? That’s where development and differentiation come in. Life begins with a fertilized, undifferentiated egg. As this cell divides and divides again, separate groups of the resulting cells begin to differentiate themselves. Each line of cells that branches off develops a genetic structure unique to itself but that doesn’t involve changes to its DNA. These altered structures are due to epigenetic changes. Different developing tissues and organs have distinctive patterns of “loosened” histone proteins that make different sets of genes available for transcription. And different sets of genes have altered methylation patterns that disinhibit genes near them and allow them to be read out. The DNA sequences in different cells are the same, but not their epigenetic context (there are exceptions; some highly specialized cells undergo late-developmental DNA rearrangements).

Tissue-specific gene regulation also includes complex networks of proteins and other molecules that control the expression of specific genes, although these are not usually included in the definition of epigenetic changes. For example, a cell might have receptors that recognize the hormone insulin, which transmit that recognition event as a signal inside the cell, giving rise to a hormone-dependent, tissue-specific response. This network of regulatory factors is specific to the cell type, and is itself a product of regulated expression.

The changes that control the developmental fate of different cells are epigenetic; they don’t involve changes in the sequence of bases in the chromosomal DNA, but they do affect genetic readout. The contentious question today is not whether epigenetics matters; of course it does, otherwise you wouldn’t have a left thumb, or a liver, or blood cells, or all the rest of your intricate bits. The issue being hotly debated is whether epigenetic patterns are “transgenerational”; in other words, are epigenetic patterns of the parents passed down to their children? This is the issue central to the discussion about the effects of the Dutch Hongerwinter. Did the stress of starvation, resulting in small birth-weight babies, then get passed, somehow, to the chromosomal structures of the next generation, resulting in health problems for that generation as well? Before considering that question, it’s worth looking at the history of transgenerational epigenetics.

The fraught history of transgenerational epigenetics

The standard model of biological inheritance is that genes determine the phenotype, or physical nature, of an organism. This model grew out of a fusion of Darwinian evolution, Mendel’s theory of genes (as we call them), and the modern understanding of how genetic systems work. According to Mendel, the factors determining biological inheritance, what we call genes, are passed down through generations largely unchanged. The biological variation observed is due to sexual reproduction — male and female parental genomes are mixed to produce an individual’s genetic content. Selection then favours the “best” genetic components under given circumstances, resulting in Darwinian evolution. (The modern synthesis of genetics also included the circumstance that a wide variety of genetic and phenotypic possibilities already exist in the population, making selection and evolution relatively rapid.) This formulation has existed since the early part of the twentieth century, and has served us well.

But before there was Mendel, or Darwin, there was Lamarck. Lamarck, a French naturalist born in 1744, had a first rate scientific mind. After distinguishing himself for bravery in the Pomeranian War (with Prussia), he studied Medicine, and then Botany. He became an academic biologist, who believed that organisms slowly evolved into more complex forms, partially prefiguring Darwin by 100 years. But in his formulation of evolution, it was environmental conditions that shaped the evolution of a species, and he had no idea about selection based on fitness. Moles were blind, Lamarck thought, because their black environment gradually caused a loss of vision. In his theory, the attributes gained by parents were handed on to their offspring. This “soft inheritance” is now being resurrected by protagonists of transgenerational epigenetics, and in their view it is behind the transmission of health effects experienced by the second generation of survivors of the Hongerwinter in Holland. Lamarck’s analysis of evolution was not irrational, given the state of science; in fact, he was well ahead of his time.

jean-baptiste_de_lamarck
The good Lamarckian: Jean-Baptiste Lamarck (1744-1829)

Lamarck’s argument was so compelling, even Darwin thought it was probably correct (it didn’t matter to Darwin’s monumental contribution, the theory of evolution, whether he thought Lamarckian inheritance was true or not). But Mendel let his direct experience guide his thoughts, and developed our modern view of genetics, and he was right. It was Mendelian inheritance, in which genes passed through the generations with very little change except for the odd mutation, that ignited the science of genetics some 50 years after his death (Mendel was a little ahead of his time).

When Mendel’s work was rediscovered and confirmed at the beginning of the twentieth century, the book on Lamarckian inheritance should have been quietly closed, but it wasn’t, at least, not in the Soviet Union. There, the agronomist and odd bird Trofim Lysenko hatched a theory that claimed that properties induced in, say, agricultural plants would be carried through their seeds into the subsequent generation. He subjected germinating wheat to icy water and claimed to produce from it a crop that could endure the cold of the Soviet steppe. He wrote copiously about the mistaken “Jewish capitalist anti-proletarian” notions (yes, he used that terminology, a lot) deriving from Mendel and Darwin, and did not believe in the existence or role of chromosomes. Geneticists in the Soviet Union thought he was nuts, but he had the ear of the total and complete leader, Josef Stalin, so they were fired, or sent to prison, or just quietly eliminated (gunshot, or starvation in prison were two effective routes to achieve this), while he prospered until the early 1960s.

lysenko
The evil Lamarckian: Trofim Lysenko (1896-1976)

In addition to being clueless about genetics and a sycophant, Lysenko was also a more broadly-rounded idiot. An incident indicative of his smarts was recalled by Zhores Medvedev, a Soviet researcher in ageing, and quoted by Horace Freeland Judson in “The Eighth Day of Creation”. Lysenko once demanded, “What is DNA? Show me DNA!” When a scientist did show him a sample of dried DNA, Lysenko said “Ha! You are speaking nonsense! DNA is an acid. Acid is a liquid. And that’s a powder. That can’t be a DNA!”

Lamarck redux?

Given the horror of Lysenkoism, it’s no wonder that Lamarck’s “soft inheritance” isn’t held in high regard by modern geneticists. And knowing what we do about genetic mechanisms, there really doesn’t seem to be any way for it to work. The only possibility might seem to be, that epigenetic changes carried forward from the parent could alter genetic behavior in the offspring. This mechanism, if it exists, might explain the health problems of the grandchildren of the Hongerwinter mothers. But one of the pillars of modern biology is that in sexually-reproducing organisms like us, the germ cells (sperm and egg) have had all of their epigenetic markers removed; histones are there, but any changes in them that occurred in specialized cells as part of differentiation are not. Against this background, it’s easy to see why “transgenerational epigenetic change” isn’t popular with many scientists.

Plants and bacteria, on the other hand, can be grown from non-germ tissue (the top of a carrot can be turned into another carrot), so the genetic material still carries its epigenetic patterns, and in fact plants (and bacteria) do show evidence of transgenerational epigenetic change.

It’s difficult to explain how the Dutch children’s health was influenced by their grandparents’ travails during the winter of 1944-45. If indeed it was. A close reading of the scientific paper that made such a claim (1) shows that the evidence is very slim. Firstly, comparing the grandchildren of the starved mothers to other children, there was no effect on birthweight, but they were slightly shorter, resulting in a higher “ponderal index”, a higher weight to height ratio. Not surprising given that their own mothers, who were born during the Hongerwinter, showed higher levels of obesity in adulthood. The major effect pointed to by proponents of “transgenerational epigenetic change” is that the grandchildren experienced a higher level of later-life poor health, as reported by their own parents. This is not a reliable source of data, but even if it’s true, there is no way to separate any epigenetic effect from an environmental one; those grandchildren were living in households of parents who had experienced deleterious health effects themselves. It’s important to have an open mind, but the evidence so far of transgenerational epigenetic effects in humans is not convincing.

Some evidence from the animal world is also used as support for epigenetic transgenerational change. One example is the “obese yellow mouse”, a mouse line in which the offspring have a range of disease susceptibilities due to sporadic expression of one gene in various tissues. Dietary regimens that can lead to epigenetic suppression can prevent its emergence in baby mice (see Figure). It’s a complicated model that would take a whole essay to explain and explore, but it’s definitely interesting. An easily-understandable article about it can be found here

However, it’s not strictly a transgenerational event, since the mother didn’t experience it or benefit from it, and it’s not generalizable. It stands more as the exception that proves the rule. Some random events during early development can also create epigenetic conditions that influence biological outcomes; an example is the random inactivation of one of the X chromosomes in females of all animal species. However, until more convincing data appear, it would be best to take claims about transgenerational epigenetic change with a grain of salt.

agoutimice425
Fat yellow mother and the slim brown child she birthed after a change in her diet that involved foods high in methyl groups (garlic, beets, onions, and certain nutritional supplements often given to pregnant women)

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Work cited

  1. Painter, R. C., C. Osmond, P. Gluckman, M. Hanson, D. I. W. Phillips and T. J. Roseboom. “Transgenerational Effects of Prenatal Exposure to the Dutch Famine on Neonatal Adiposity and Health in Later Life” BJOG: An International Journal of Obstetrics and Gynecology 115 (10): 1243-1249 (2008). Available online here

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