“I will call to the past, far back to the beginning of time, and beg them to come and help me at the judgment. I will reach back and draw them into me, and they must come, for at this moment, I am the whole reason they have existed at all” says the African slave freedom fighter Joseph Cinqué in Steven Spielberg’s film Amistad.
Our ancestors impart us wisdom and strength. But above all they leave a legacy in our DNA that we carry with us until we pass it on to the next generation. DNA is constant; changes are slow, they happen at a rate of approximately 1 in 30 million bases per generation. The human genome is 3 billion bases (or letters) long. Each cell contains two copies of the 3 billion-alphabet book, one from the mother and one from the father. This is the basis of inheritance.
We know why seeds of sweet mangoes grow into trees giving sweet mangoes. Why my grandmother, my mother, my uncles and I all have liver disease. That is genetics, we say. We all know what the mother eats and drinks will affect the baby in the womb. It so turns out that what the mother eats during her pregnancy can affect what diseases the baby may have as an adult. It turns out what the father drinks and eats during his life can affect the baby’s adult life. It also turns out that if the grandfather had a well-fed life then the grandchild may have a shorter life span! That is epigenetics.
In the middle 1800s a monk in Brno in the present Czech Republic uncovered nature’s secrets on inheritance by careful study and keen observation. Human beings had long noticed that children carry traits from the parents, aunts and uncles and grandparents. What Mendel did was, he systematized what he learned in his studies into rules that govern inheritance, which effectively say (1) that my genes come in pairs, one copy from each parent and the combination of the two give me the trait e.g. hair colour, height, earlobe shape etc. (2) my child will get one of these copies of each of the 20,000 or so genes from me and the inheritance of one gene will not influence the inheritance of the other and (3) some traits may be dominant, one copy will supersede over the other. Nearly two centuries later we still use these laws to understand inheritance. But now we have discovered that many traits and diseases are influenced by not just one gene but many genes. Such traits are numerous, examples include diabetes, cancer, hair colour, musical ability and so on. Hundred years or so after Mendel, biology changed for ever. In 1944 Avery identified the physical basis of inheritance, deoxyribonucleic acids, or as we all know it now, DNA. Soon after it was established that DNA was copied from one cell to another each time a cell divides. Watson and Crick led the new genomic era when they demonstrated how the structure of DNA allows the letters to be faithfully copied to be passed into the next generation.
We begin our life as a single cell in our mother’s womb and that cell divides innumerable times to grow into an organism of more than 30 trillion cells. Women will make around 400 ova in a lifetime and men around 100 million sperm in a day. Each of these cells carries a full complement of our 3-billion base long genome inside. 3 billion bases would amount to around 2 metres of length of DNA in each cell packed into a nucleus of 6 micrometre diameter. DNA binding proteins known as histones help wrap this DNA into a manageable size for the cells. However, the DNA cannot be archived away in the attic like you would do with your grandfather’s massive dusty library. The DNA contains instructions on making various proteins, the functional machinery of the cells. When a cell needs to make a particular protein, say insulin in the pancreatic cells, the gene for insulin needs to be unpackaged and opened up so the cell can read the instructions. How does the cell know where the gene for insulin is, in all the 20,000 or so genes in our genome?
This is where epigenetics comes in. The cell employs a number of enzymes for the library management i.e. tagging genes for easy identification and access. Enzymes such as Histone Acetyl Transferases (HATs) would put an ‘ON’ tag on the insulin gene in all pancreatic cells; an easy solution, so the cell can find the instructions and make insulin as and when needed. The same insulin gene would be given an ‘OFF’ tag in a brain cell, where it is not needed.
Epigenetic messages from cell to cell
When a pancreatic cell is born, the insulin gene will be tagged ‘ON’ in the DNA. Each time this pancreatic cell divides to give two ‘daughter’ cells, the daughter does not have to relearn this rule. The mother passes a message on to the daughter that says something like ‘you are a pancreatic cell and your insulin gene should always be tagged ON’. This kind of cell-to-cell epigenetic messages help cells achieve and maintain their function at the right time and in the right amount. When such instructions fail and cells do not switch on the correct genes are the right time, disease results.
Acute myeloid leukaemia is an extremely aggressive form of blood cancer. Blood contains many different kinds of cells that are important for carrying oxygen (red blood cells-RBC) and those that protect the body against infection (white blood cells-WBC). The bone marrow stem cells form RBCs and WBCs through a strictly orchestrated series of events. The stem cells start with ‘pluripotency’ (or potential to make multiple cell types) where the stem cell genes are ON. As they ‘differentiate’ to form RBC or WBC they would switch OFF the stem cell genes and switch ON the haemoglobin gene (in RBCs) or the immunoglobin gene (in WBCs). When the epigenetic ON-OFF program goes awry, you end up with cells that continue to be in ‘stem-cell’ state and do not form RBCs and WBCs appropriately. These cells start dividing uncontrollably and viola! you have cancer.
Epigenetics messages from parents to children
Babies with Prader-Willi syndrome have severe feeding problems and do not gain weight as an infant. As they grow into childhood they develop insatiable appetite, obesity and associated diseases such as diabetes and hypertension. They also have behavioral problems and mild intellectual disability. Prader-Willi is an epigenetic disease.
Just as each cell type in the body has unique marks, the DNA in the sperm and ovum too have unique marks on them. When the sperm and ovum fuse in the mother’s womb to form the embryo, the embryo inherits these marks. As I mentioned earlier, genes come in pairs, one from mother and one from father. For the Prader-Willi gene, the maternal copy is pre-marked as OFF, only the paternal copy is ON. This process of information passed on from parents to children is called ‘imprinting’.
Sometimes random mutations or changes happen in the Prader-Willi gene in the sperm or ovum. If it happens in the ovum, the baby is born normal; the maternal copy of the gene is after all always OFF. But in the event that the mutation happens in the sperm, then the baby inherits a non-functional gene from the father. The paternal copy is the only ON copy of the gene. This is equivalent to the baby now not having any normal copy of the gene and thus develops the Prader-Willi syndrome.
Epigenetic messages from across generations
The most intriguing aspect of epigenetics is transgenerational inheritance. Effect of environment on one generation is passed on to the next and the next generation e.g. children of men who were undernourished in their mother’s womb grow up to be more obese as adults than children of men who were born to well-nourished mothers.
In 1945, during the Second World War, Germany occupied western Netherlands. In retaliation to the Dutch support to the Allied Forces, Germany blockaded the shipment of food into Netherlands. A harsh winter and the blockade led to a famine in these regions that was relieved only after the Allies regained the western provinces of Netherland. The Dutch, including women who were pregnant, suffered severe malnutrition during this time, in 1945. In 2013 a group of scientists published the results of a study on the children and grandchildren of the Dutch famine victims. They found that children who were exposed to the famine in their mother’s womb had increased propensity for a number of diseases and had abnormal epigenetic marks even at sixty years of age. They also found that women born to famine-exposed mothers had more babies themselves. And even more interestingly, children of men who were in their mother’s womb during the famine were more obese as adults and had higher body mass index (BMI) compared to grandchildren of women who were pregnant during 1944 or 1946, the non-famine years. Epigenetic changes in one generation that was exposed to famine perhaps made them more reproductively successful and the next generation more able to store away the food they get.
Evolution operates on the principle of natural selection. Our DNA accumulates changes over generations, many of them, which do not affect our lives at all. However, the environment in which we live changes. Droughts and famines, ice ages and epidemics ravage us, challenge us, constantly. The individuals who weather these storms better, because those previously silent changes in their DNA help them cope better, survive.
Perhaps epigenetics allows us to adapt faster to the environment even when we are not genetically the fittest. Perhaps epigenetics is the helping hand extended from our ancestors to push us across when nature creates fissures in our path. After all, we are the reason they existed at all.
This article appeared in the Manorama Yearbook 2015
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