The embryo develops by the cellular division of a single cell. In animals, embryogenesis defines the transformation of an egg into an embryo. The first stages of embryonic development are called morula (8-16 cells), blastula, gastrula and neurula. In humans, the term foetus is used after the third month.
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A word created in the 19th century and redefined by Conrad Waddington in 1942 to take its modern meaning, epigenetics is the study of the influence of the cellular and physiological environment on the expression of our genes.
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The power of genes called into question
On analysing the results – only 10% of the genome codes for proteins – the extent of the power of our genes has been seen in more relative terms. In other words, simply examining the genome would not allow explaining the occurrence of such and such a disease. This was not a total surprise for developmental biologists, since we know that a complex and complete multicellular organism can be developed from only one cell, a fertilised egg containing a specific genome. From one division to another, DNA does not change though the cells acquire specific functions (see the article on stem cells). Each type of cell expresses different genes at specific moments. Different factors and different proteins are produced by certain cells but not by others, or only at specific moments while certain coding genes “switch off” at other moments.
There is another dimension in which genes can provide responses – or at least the beginnings of responses – to their differentiated expression in time and space. Changes in the level of DNA (DNA methylation and histone acetylation) lead the genome to be read differently from one cell to another and these different readings can be propagated stably.
Conrad Hal Waddington, a British scientist and philosopher born in 1905, observed that thermal shocks to the fly led to multiple malformations that could be found in the fly’s offspring. At that time, Waddington assumed that these shocks revealed hidden mutations, inherited in their new form. He was the first to formulate explicitly the need to establish causal links between genotype and phenotype to understand the development process. Thus he brought genetics – the science of heredity –, and epigenetics – the theory of development, closer together through the progressive elaboration of forms.
Epigenetics today consists of the study of the changes that modify gene expression without mutation of DNA, heritable and reversible changes that are transmitted outside genes. Epigenetics stand at the crossroads of the disciplines of genetics, developmental biology, ecology and evolution.
Genetics and unanswered questions: the responses of epigenetics
How, why, when?
- How can our cells, resulting from the division of a single cell and endowed with the same genetic heritage, be so different according to whether they constitute the eyes, a muscle, the skin or the brain? It must be assumed that a higher level of regulation exists between the genes and the characteristics they code.
- In 1999, the geneticist Emma Whitelaw at Sydney University (Australia), showed for the first time that an epigenetic modification can be transmitted to offspring. She identified mice that were genetically identical but with different coats. The mice with brown fur were normal, the mice with yellow fur had cancer, diabetes and were obese. This diversity was due to the epigenetic variability of a gene. In 2003, Randy Jirtle, an American biologist born in 1947, known for his pioneering research in epigenetics, showed that by feeding these gestating mice with food rich in methyl donors, the number of obese yellow individuals fell in the young. It was therefore possible to modify the epigenetic marks.
- There are two copies (alleles) of each gene, one transmitted by the mother and the other by the father during fecundation. They are most usually expressed together, indifferently, but sometimes only one allele is expressed, while the other remains inactive, “mute”. The characteristic expressed can vary since the maternal and paternal allele can carry different epigenetic marks.
- Epigenetic marks may also play a mental role. In 2004, Canadian researchers showed that racoons raised by attentive mothers were more resistant to stress when adult than racoons that had received less attention.
- The enigma of identical twins: “But you seem so different!”
In spite of having an identical genetic heritage, identical twins can exhibit physical differences, such as a rounder face, different beauty spots, etc. Once may develop a disease not contracted by the other. How can these differences be explained? Some genes may be active only in one of the two twins. These differences have also been seen to accentuate with age and identical twins to diverge as their lives progress, especially if they adopt different lifestyles. Thus, although they can be genetically identical, they are not “epigenetically” identical.
From molecular to ecological scales, an environment with a strong impact
In 2005, the researchers Marcus E Pembrey and Lars Olov Bygren (clinical geneticists at the Institute of Child Health) demonstrated that the dietary habits of grandparents could have consequences on their grandchildren.
The environment of genes is formed:
- within, by:
- outside by:
- our diet,
- our activities,
- the place where we live,
- our environmental and professional exposure (physical, chemical and biological agents, etc.).
Although our lifestyle and conditions of existence influence our mental and physical health, they can also modify the functioning and expression of our genes inherited from our parents at birth.
The genetic code orchestrated like a musical score by epigenetics
Epigenetics concerns the influence of the cellular and physiological environment and individual history on the expression of our genes.
This discipline seeks to explain how the modifications that are not coded by the DNA sequence DNA (methylations, prions, etc.) can regulate the activity of genes by facilitating or preventing their expression. Indeed, the nucleotide sequences (DNA) that compose certain genes is not modified. However, the proteins coded by these genes can be produced at different times or places according to the epigenetic marks that may or may not be present on the genes. It is considered that these marks result from the environment of a gene.
It is rather like a musical score coordinated by an orchestra conductor who gives a specific colour and tempo to the interpretation, probably different from those imagined by the author. As in epigenetics, the orchestra conductor gives consistency to the playing of all the musicians/genes; he adjusts the balance between the different acoustic masses of the orchestra/organism.
Genes controlled by a series of switches: even the orchestral interpretation of music is modulated by silences
Our environment, from molecular to ecological scales, is susceptible to modify the expression of our genes which are controlled as if by a series of switches.
Enzymatic reactions can “silence” a gene, that is to say inhibit its expression. Even in music, orchestral interpretation is modulated by silences that must not be underestimated.
As the cells develop, their fate is governed by the use selective use and silencing of genes. This process relies on epigenetic factors.
The methylation profiles of DNA and the acetylation of histones appear to play roles in all kinds of phenomena where genes are activated or deactivated.
Epigenetics play a role in:
- the adaptation of living organisms to environmental conditions;
- physical differences, behaviours and the development of diseases in identical twins;
- the process of cellular differentiation that allows a single cell to produce the 200 families of cells that form our bodies. It should also be remembered that a caterpillar and its butterfly have exactly the same genes;
- and more besides.
Certainly, it is possible to compare the distinction between genetics and epigenetics to the difference between writing and reading a book. Once the book has been written, the text (the genes or the information stored in DNA form) will be the same in every copy distributed to the public. However, each reader of a given book will have a slightly different interpretation of the story, which will stir their emotions and personal reflections chapter by chapter. In a very similar way, epigenetics may permit several readings of a fixed matrix (the book or genetic code), giving rise to different interpretations according to the conditions in which the matrix is questioned.
Thomas Jenuwein (Max Planck Institute of Immunobiology and Epigenetics – Fribourg – Germany,)
Epigenetics, a medical and scientific challenge
Acording to the cancerologist Zdenko Herceg, of the International Agency for Research on Cancer (IARC – Lyon), “epigenetic changes and genetic mutations are present in all types of cancers, but their interactions are so complex that it’s difficult to know the initial events”.
We now know that very different chemical processes play a role in the development of many diseases, including cancer. These processes are also involved in the behaviour, aging and longevity of individuals. All this leads to saying that epigenetics, an area of research undergoing rapid expansion over the past few years, is one of the major scientific and medical challenges of our time.
Jean Pascal Capp, a doctor specialised in molecular cancerology, and associate professor at the Institut National des Sciences Appliquées (INSA) of Toulouse, wrote in the article “Cancer under the influence of the environment”: “Epigenetic changes do not affect gene sequences themselves but their expression, by way of chemical and structural modifications of chromatin, a thread that can be likened to a pearl necklace formed by a DNA molecule and the proteins bound to it. For example, cancer suppressor genes and those involved in repairing DNA are inhibited. The cell thus has even less freedom to control its divisions or prevent mutations. In other cases, these modifications can reactivate inactive genes, thereby contributing to the proliferation of cells in the tumour. Epigenetic instability will be as intense in carcinogenesis as in the epigenetic instability itself. Nonetheless, epigenetic changes are transient and subject to rapid random variations. This leads to the fact that the characteristics of tumour cells can vary within the same tumour”.)
Epithelium: the tissue coating all the internal and external surfaces of the body. It is composed of cells called epithelial cells of variable shape and arrangement.
The epithelium is a tissue that covers all the surfaces of our organism, on both the outside (skin, mucous membranes, natural orifices) and the inside (thoracic cavity, digestive tract, etc.). It can also constitute glands.
An epithelium is composed of cells called epithelial cells that are arranged closely together.
The number of cells, shape and arrangement depend on the type of epithelium.
The function of the epithelial cells differs according to the organ they cover: protection against the external environment (e.g. skin), sensorial reception (e.g. skin), mechanical protection (e.g. esophageal epithelium), secretory epithelia for chemical protection (e.g. gastric epithelium), absorption (e.g. intestinal epithelium), movement (e.g. respiratory epithelium and the epithelium of the Fallopian tubes), substance exchange (e.g. capillary epithelium*)…
(*small blood vessels)
The capacity for a cancer to escape the control system of the human body (immune system), and create metastases in other parts of the body.
Further information :
Our organism possesses mechanisms that are activated at cellular and molecular level to combat the onset and development of a cancer. However, these mechanisms are sometimes diverted by cancerous cells.
The organism is monitored by the immune system
The cells of our organism are under constant surveillance by the immune system.
It is like an anti-missile defence system with homing devices, radar systems and drones. The immune system is responsible for checking whether our organisms is infected by an aggressor (pathogenic agent) or invaded by abnormal cells as in the case of cancer. It is the defence system that acts to protect us against diseases, poisons, and pathogenic agents like viruses, bacteria and parasites.
This surveillance is ensured by the presence of molecules on the surface of the cells: these fragments are called antigens.
A healthy cell has antigens on its surface that are recognised as belonging to our organism: the self. This recognition can be performed by the effector lymphocytes of the immune system which have a receiver on their surface.
The antigens on the surface of a cancer cell have been modified. These foreign antigens are recognised by the effector lymphocytes as alien to our organism. Thus they are activated against the cancer cells and eliminate them.
The mechanisms of escape from the immune system
The cancerous cells can escape the surveillance of the immune system in different ways:
- The cancer cells may no longer present antigens on their surface. These cancer cells therefore become “invisible” and can no longer be eliminated by the immune system.
- Certain cancer cells may be slightly immunogenic, which means that their capacity to activate the immune system is weak. They present few or no foreign antigens on their surface and above all present self-antigens. Consequently, these cells are well equipped to escape the surveillance of the immune system and can develop and circulate more easily.
- The cancer cells can also escape the surveillance of the immune system by impeding its action against the cancer. In this case, the cancer generates an immunosuppressive microenvironment that prevents its infiltration by the cells of the immune system.
- The cancer can also promote the recruitment of the cells of the immune system that inhibit the anticancer immune response such as macrophages and regulatory lymphocytes.
These strategies for bypassing the immune system allow the cancer to develop beyond any control.