A deep dive into the gene pool to understand epigenetics and epigenomics
This plot line of the 1997 American science fiction film Gattaca may or may not become reality, but it brings into focus a tiny double-stranded particle that knows our most intimate secrets
In the not-so-distant future, libertarian eugenics is common. A genetic registry database employs biometrics to categorise those so created as “valids”, while those conceived through traditional means and more prone to genetic disorders are known as “in-valids”. Genetic discrimination is illegal, but genotype profiling is used to identify valids to qualify for professional employment while in-valids are relegated to unskilled jobs.
This plot line of the 1997 American science fiction film Gattaca may or may not become reality, but it brings into focus a tiny double-stranded particle that knows our most intimate secrets. DNA, or Deoxyribonucleic acid, is the molecule of heredity. It was first isolated by Friedrich Miescher in 1869 and its molecular structure was first identified by Francis Crick and James Watson at the Cavendish Laboratory of University of Cambridge in 1953. The molecule is built up of little units called nucleotides or bases (there are four different types in DNA) and the sequence of these bases encodes all our genetic information. This sequence can be read by sophisticated decoding machinery present in every cell in the body and it is this sequence that is “translated” into the sequence of amino acids (building blocks of proteins) that makes up a particular protein. These proteins in turn create the structure and function of every cell. The elucidation of this code and the machinery that decodes it is one of the great triumphs of modern biology. But this triumph immediately raises new questions: the DNA code is faithfully copied in every cell division. We start with one fertilised cell (formed by the union of an egg cell and a sperm cell) and this cell repeatedly divides until we end up with the several trillion cells that make up an adult human body: the exact number remains a matter of dispute, but it is perhaps around 35-40 trillion. Every single one of these cells carries the complete DNA code present in the first cell. Yet every cell is not alike. There are some hair cells that make hair, nail cells that make nails and many kinds of brain cells that make brains. Obviously they are not all alike and yet their DNA is identical. How does the cell know what kind of cell it is supposed to be?
The answer is ‘epigenetics, literally meaning ‘on top of genetics’. Our long DNA molecules, three billion base pairs in all, are wound around protein cores called histones and only parts of the DNA are unfolded in any given cell. This unfolding is partly determined by chemical changes in the histone molecules. Within the parts that are unwound, and therefore available to be read by the decoding machinery of the cell, the DNA molecule can also be modified by adding methyl groups to one of the bases – converting cytosine into methyl cytosine – which can change how that segment of DNA is translated by the decoding machinery. These and other chemical alterations that can affect how DNA is unwound, decoded and translated are all grouped together under the term ‘epigenetics’. Thus, a hair cell makes hair because epigenetic changes have made its hair-producing genes very active, while suppressing countless other genes that are not needed in a hair cell. Meanwhile, the nail cell has its nail genes active and many other genes suppressed. This selective turning on or off of functional segments of DNA, i.e. genes, is carried out by multiple mechanisms, of which histone modification and methylation are two of the best studied examples.
Now, when the dividing cells in an embryo reaches a point where hair is supposed to grow, then the stem cells, or ‘mother cells’, of that region produce ‘daughter cells’ that all express hair-related genes, but do not express nail-related genes or genes responsible for the production of any other tissue. Somehow the epigenetic code has been modified and this modification is inherited by all the subsequent hair cells. Thus, the epigenetic code can itself be inherited by daughter cells within that organism, but when this baby grows up and produces sex cells – eggs or sperm – most of these epigenetic marks are erased and we start afresh. But not all marks are erased as we move from one generation to the next. Some epigenetic modifications do seem to be passed on to the next generation or even two to three generations, though not to subsequent generations. Just as epigenetic marks can be added to DNA to modify its function – to turn genes on or off, to make them more or less active – these marks can also be removed. Unlike the genetic code or genome, which is passed on unchanged except for occasional mutations and modifications in every generation, the epigenome is constantly changing and can be modified by drugs, nutrition, stress and countless other factors. Thus our cells are not just programmed by their genetic code, their structure and function is modified by epigenetic changes that can alter how the cell functions.
This dynamism can be overstated though. Many pseudoscience gurus, and some scientists, feel that a fixed genetic code is too deterministic. Why can’t we change ourselves by our own efforts or the efforts of our peers and parents? Epigenetics seems to offer such a possibility and so it is no surprise that every quack on the internet is selling it as the miracle cure to genetic determinism. But this is misguided. We have always known that the effects of genes are modified by the environment, but that does not mean they are infinitely malleable, nor does it mean there is some alternative mechanism of heredity that can be altered as we please, even in theory. Epigenetic modification is a normal part of life, but it does not change the genetic code and even if some rare aspects of it are inherited for one or two generations, these modifications are neither permanent nor hugely impactful. Epigenetics, in short, is the biological counterpart of the physicists’ ‘quantum’, and just like that catchy term, its use in popular culture is mostly hype, or misunderstanding.
That said, it is still hugely important. Epigenetic modifications make every cell into a particular type of cell, and dynamic changes in the ‘epigenome’ – the sum total of epigenetic changes – can mediate the lifelong or even transgenerational actions of major perturbations such as starvation, high blood sugar, chronic abuse, etc. Babies born to malnourished mothers are at higher risk of diabetes and obesity, i.e. their system has been ‘programmed’ to hold on to fat and to be insulin resistant. This programming is not fully understood yet, but it is very likely to be epigenetic. Similarly, babies whose mothers suffered from chronic stress can have an exaggerated stress response all their life; another example of epigenetic programming. If various insults can create such programming, then other interventions – diet, medication – can also alter this programming, changing the risk of future disease.
Another important area of study in epigenetics is cancer. Many cancers seem to arise because of changes in the epigenome, for instance changes that cause cancer-suppressing genes to be suppressed, or cancer-promoting genes to be activated, and it may be possible in the near future to scan for these changes and to intervene – with diet, with drugs – to reverse them and thus to change the course of cancer in that patient. The gradual accumulation of ‘bad’ epigenetic changes may also be one of the mechanisms by which our bodies weaken and malfunction as we get older. Epigenome scans may detect these changes and one day we may be able to intervene to prevent or reverse the effects of aging.
The Indian subcontinent is the world’s largest reservoir of malnutrition and low birth weight. The burden of these harmful processes may be one of the reasons behind the high incidence of diabetes and other metabolic disorders in people of Indian origin. Epigenetic mechanisms almost surely play a role in these diseases and advances in epigenome sequencing and scanning are beginning to illuminate these processes and may soon enable us to intervene to protect the health of future generations. But it is worth repeating that the low-hanging fruit is in public health measures – clean water, sanitation, nutrition, vaccination, prenatal care – and the impact of epigenetic knowledge is likely to be relatively limited in the near future. Several Indian scientists have contributed to the DNA revolution, including Nobel Laureates Hargobind Khorana and Venkatraman Ramakrishnan, and others are working on cutting- edge aspects of biology all over the world. ‘Gattaca’ or not, as India progresses in science and technology, more and more such stars will shine within Indian research institutes as well, and will no doubt play a vital role in the coming epigenetic revolution.
The author is a pediatric endocrinologist with a research interest in the genetics and epigenetics of obesity
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The team believes the artwork was made by Homo sapiens, as opposed to now-extinct human species like Denisovans, but cannot say this for certain.
When a mutation happens in the first few weeks of embryonic development, it would be expected to be widespread both in an individual's cells and in those of their offspring.