|Epigenetics – Turning genes on and off|
The BBC Horizon documentary The ghost in your genes, successfully explains a particularly complex field of science. Genetic inheritance has historically been thought of as involving the transmission of DNA from one generation to the next affected by occasional mutations in the DNA itself (00:04:37 – 00:05:50). “Up to now, inheritance is just the genes, the DNA sequence. I suspect that we’re going to be able to demonstrate that inheritance is more than that”, explains Professor Marcus Pembrey from the Institute of Child Health, UCL. A few scientists had hypothesised that the conventional genetic model and mode of inheritance was too simplistic to explain the complexity of human beings. The revelation that the human genome likely contains only about 30,000 genes (00:08:54 – 00:11:33), coupled with increasing experimental evidence, now leads scientists to believe that other factors allow genes to be switched on and off in response to environmental stimuli. The consequences of which may affect subsequent generations.
|Professor Marcus Pembrey|
In the early 1980s, Professor Pembrey was Head of the Clinical Genetics Department at Great Ormond Street Hospital, London (00:05:50 – 00:08:58 and 00:11:33 -00:16:47). He was often presented with families exhibiting unconventional genetic inheritance patterns. This drew his attention to two genetic diseases;
- Angelman syndrome, which displays clinical symptoms of jerky movements, little or no speech and a very happy personality
- Prader-Willi syndrome, patients are found to be very floppy in infancy and develop an insatiable appetite associated with obesity in later life
|‘Pint’ hexagon shape represents an imprint on the human genome|
He worked out that these two completely different diseases were caused by the same genetic alteration, a small deletion on chromosome 15. What was even more remarkable was that the parent from whom the mutation was inherited determined which disease was observed in the patient. If it was inherited from the mother then the child would have Angelman syndrome; from the father then the child would have Prader-Willi syndrome. This phenomenon suggested that the chromosome somehow ’knew’ its origin and therefore must be tagged or imprinted in some way – this has become known as ‘genomic imprinting‘. During sperm or egg production, a chemical change results in the same DNA sequence on each chromosome having different functional properties. These events can lead to a particular gene being turned on or off, and this is the central principle underlying ‘epigenetics‘.
|Professor Wolf Reik|
Professor Wolf Reik, Developmental Geneticist, Babraham Institute Cambridge (00:16:46 – 00:24:05), helped unravel the control process. He noticed that when a mouse embryo was placed in a culture dish some of genes would be switched off and wondered whether this could also be true for human embryos during In vitro fertilisation (IVF).
Beckwith-Wiedeman syndrome (BWS), which is typically characterised by the excessive growth caused by reduced expression of a growth-suppressing gene and increased expression of a growth-promoting gene, is another epigenetic disease. These genes, which are found on chromosome 11, usually work in tandem to ensure correct and proportional growth. In the disease state, epigenetic changes cause this to become unbalanced, leading to excessive growth of the patient.
Professor Reik discovered that BWS occurs more frequently in IVF-conceived children than with natural births. This evidence suggests that placing a human embryo in a culture dish and thus changing its environment, could induce an epigenetic alteration, causing genes to be turned on and off. Professor Reik also showed that the epigenetic changes observed in mice could be inherited from one generation to another.
|Professor Rachel Yehuda|
To establish whether an environmental stimuli could imprint inheritable change on DNA in humans, the documentary examines the work of Professor Rachel Yehuda, Mount Sinai School of Medicine, New York and Professor Jonathan Seckl, Edinburgh University (00:28:19 – 00:35:46). Both were interested in ‘transgenerational effects’, in which an event could happen in one generation and be transmitted non-genetically to the next generation. Professor Seckl’s work on pregnant rats had shown that exposure to stress hormones caused raised anxiety in their offspring, and in generations thereafter.
|BBC News report on research|
Their work examined the impact the September 11th 2001 terrorist attacks in New York had on pregnant women. The human ‘stress hormone’ cortisol, is involved in the human response to stress. Low levels detected in the saliva are associated with difficulties coping with stressful events which may induce a Post Traumatic Stress Disorder (PTSD). Pregnant women in the last third of their pregnancy at the time of the attacks on the Twin Towers and who suffered with PTSD not only had low levels of cortisol but also their children were born with lower than normal levels of cortisol in their saliva as well. This indicated that events during the last third of a woman’s pregnancy could change their children’s ability to cope with stress. To confirm that this was an epigenetic change, both scientists admit that they will need to examine the cortisol levels in the next generation, to see whether this change has in fact been inherited and is not just a consequence of high levels of cortisol in the mother’s womb.
In search of further evidence of the epigenetic phenomenon, Professor Pembrey teamed up with Swedish Professor Lars Olov Bygen, The University of Umea (00:23:46 – 00:28:19 and 00:35:16 – 00:43:18). Their work focussed on the remote Sweden town of Overkalix. The town has an extensive archive of population records, including all births and deaths of people who have lived there and, crucially, harvest information going back hundreds of years.
|Professor Lars Olov Bygen|
At first they found that life expectancy of grandchildren was directly affected by the diet of the grandparents. Fatal childhood diabetes was often associated with their father’s father living during a period of reduced food supply. In a further development, the records revealed that triggering of a trans-generational effect was dependent upon the time in the grandparents’ lives when food had been in short supply. For the grandfather it was just before puberty and for the grandmother it was the moment of conception, crucial moments in the development of sperm and egg. These observations suggest that environmental information, in this case supply of food, was being imprinted on the DNA of the sperm and egg, providing strong evidence that epigenetic inheritance occurs in humans.
|Exposure to pesticides and its epigenetic affect on offspring|
In further work, Mike Skinner (00:43: 18 – 00:45:51) exposed a pregnant rat to a high dose of a common pesticide. He found that the offspring passed on an array of diseases, such as; tumours, kidney disease and immune dysfunction from generation to generation. This evidence suggests that there are a whole series of environment events that might possibly trigger transgenerational affects and effect future generations.
Ethics of epigenetics
|Lifestyle choices and epigenetics|
The understanding of mechanisms by which environmental events can induce transgenerational effects is significant. The gender of the parent passing on a mutation, use of IVF, mental trauma, food supply and pesticide use have all been implicated as epigenetic triggers. It is highly likely that other lifestyle factors may leave people susceptible to epigenetic changes, with alcohol consumption, drug taking, smoking, exercise, stress at work and atmospheric toxins amongst the most probable candidates. As such, this raises many ethical issues for discussion;
- Epigenetics may demonstrate that people have a choice concerning the influences to which they ‘expose’ their genome. Should there be obligations concerning the lifestyle decisions of the current generation for the sake of future progeny?
- Will individuals be legally culpable for future illness in their offspring if an established link is ignored?
- Will epigenetics lead to multigenerational liability for mortgages, employment or insurance? Will environmental events in previous generations lead to higher premiums for the current generation?
- Should women be prevented from working in the later stages of pregnancy to preserve future generations?
- Would epigenetics lead to issues of discrimination?
- Is the information contained within the human genome more or less sensitive now that scientists recognise epigenetic influences? How and who does this information effect? Should it be protected by privacy legislation?
- What effects could epigenetics have on compensation payments? Environmental justice – workers, home owners, car driver are exposed to different substances. What health effects will this have on future generations?
- Epigenetics will highlight social inequalities – those that could be affected most are those who have the least hospitable home and work environments and least access to full and proper health care.
‘The ghost in your genes’ is an excellent resource to help explain the basis of genomic imprinting and epigenetics. Despite never directly discussing the ethical issues surrounding the topic, it does make many references regards to the possible implications epigenetics may have for future generations. It also acts as a very thought provoking documentary regards the rights and wrongs of the research and the consequences such findings may have.
This Horizon episode was first broadcast on 3rd November 2005, BBC 2, 21:00pm, 50 minute (TRILT Identifier 005536A3) and was repeated 10th November 2005, BBC1, 02:05am.