Post by NZBC on Dec 3, 2012 20:28:58 GMT 12
Epigenetics: navigating our inner seas
Renee Liang
Creative non-fiction
Science lets us see the way nature is; we experience this as we glimpse the workings of the same great celestial clock James Cook saw when the transit of Venus began at the predicted moment in June 1769. Science is the compass on the voyage we must all make into the twenty-first century. That we have it in our possession is astonishing. That we should never have found it, or that we should turn our back on it, is quite simply unthinkable.
Professor Sir Paul Callaghan (1947-2012)
It’s the middle of the night and I’m up once again for a feed. Sofia, a chubby 2-month-old bundle, smiles confidently up at me as she opens her mouth, but I’m too preoccupied until I remember and quickly smile back. Be present. Show your love.
It seems to be the lot of the modern parent that they’re constantly swimming in guilt. Am I eating the right diet to make good breastmilk? Are we stimulating, sleeping, burping her enough? As a researcher, I believe in science as a foundation for health. But as a mother, I find all this scientifically-validated advice restrictive – and, I’ll admit, a bit nannyish. From the moment I thought I might be pregnant, I’ve been bombarded with information on what (not) to eat, how to exercise, what to read. Midwives, Plunket nurses and Karitane
2
visitors invite themselves around. I have fridge magnets with phone numbers, free government-sponsored DVDs, and stacks of books next to my feeding chair. I don’t read them because Sofia looks at me and I smile – because I want to, not because of what the books say.
Is science really the compass that will help me guide my daughter to her brightest future? You only need listen to ‘helpful’ grandparents to work out that baby advice follows trends, like everything else. But with the explosion of research into early human development, that advice has snowballed. Epigenetics is emerging as potentially one of the most significant fields of study.
For over half a century it’s been known that a mutation – a tiny slip-up in the precise process of DNA transcription or copying – can lead to catastrophic disease. Mutations are also the process by which the human blueprint spontaneously changes, serendipitously adapting us to changing environments. Coupled with natural selection, these form the basis of evolution. Sadly, the individual in whom this takes place does not enjoy the benefits of being a freak. The process takes many generations. Unfortunately we live in an era where environmental change seems to ride an ever-steeper logarithmic curve. Traditional evolution won’t work in time to save us from ourselves.
However, there’s a little ray of light. The idea that we can adapt quickly to our environment, then pass on these attributes to our children, has long been poo-pooed by the establishment (ironically, led by one Charles Darwin.) It turns
3
out that Darwin’s great rival Lamarck, once consigned to history’s bin of discredited scientists, may well get the last laugh.
Epigenetics is a term first coined by developmental biologist Conrad Waddington in 1942 - interestingly, predating Watson and Crick’s 1953 elucidation of the structure of DNA. Epigenetics refers to the idea that an organism’s experience alters the expression of its genes. This happens through the application of ‘tags’ over (epi) the genetic blueprint. This affects the way DNA is then read. To use a simple metaphor: if nucleotide bases are an alphabet, genes the words and a strand of DNA a sentence, then epigenetic tags are the punctuation.
Since all cells in a body carry the same copy of DNA, something is required to tell each cell which bit of the DNA to use. There are codes and switches embedded in the DNA itself, but epigenetic tags act as a kind of external add-on.
Two types of tags have been identified to date. Methylation, the attachment of methyl chemical groups to certain points on the DNA blueprint, causes the reading machinery of the host cell to skip. This affects which proteins are manufactured and therefore how that cell functions – a process known as translation. Proteins called histones also change the reading of DNA by ‘spooling’ or winding the strands of genetic material. DNA must be unspooled in order to be translated. In effect, methylation tells the cell what to read, and
4
histones change the speed of reading. The underlying structure of the DNA remains unchanged.
What are some of the real-world consequences of epigenetic tagging? It’s early days, but already there are tantalizing clues. Canadian scientist Michael Meaney has recently shown that rat pups frequently groomed and licked by their mothers have a better response to stress as adults than rat pups who are cuddled less. Meaney has also shown that these differences are due to changes in gene expression.
So how does Meaney’s research translate to me in the real world? If my daughter misses out on a look or cuddle because I am too busy checking emails, will this lead to her being unable to cope in later life? Talk about motherly guilt!
Of course, it’s a long way from animal experiments to the complexities of human social interaction. As scientific papers are fond of pointing out, more data is needed. But it’s tempting to extrapolate. It’s long been observed, both anecdotally in and formal studies, that children deprived of physical or emotional nurture in early life respond more poorly to stress as adults. It’s also been assumed that the path from poor nurture to a misspent adulthood must be a complex web of many different factors. But what if (playing the devil’s advocate), it was just due to the vandalism of a few wrongly-tagged genes? Would modern medicine then be able to develop a quick fix, an anti-poverty pill? Governments the world over would breathe a sigh of relief.
5
This does seem to take the science too far, at least for now. But research on humans supports the idea that maternal behaviour is important. New Zealand scientists at the Liggins Institute, world leaders in the field of early human development, have discovered that how a mother eats during pregnancy – specifically during the first trimester - can affect the health of a foetus through its life. A child born to a mother with a poor diet is more likely to suffer from early puberty, eat more fatty foods, be less likely to exercise and suffer from heart disease, high blood pressure, diabetes and obesity. A child born to a mother with an overly rich diet fares even worse in terms of future disease.
The first thousand days, from conception to the second birthday, is known to be critical to a child’s development. It is in this period that crucial brain connections are made and cells differentiate into their specialized roles. This is also when the genetic blueprint is most susceptible to epigenetic tagging. Researchers have found that DNA methylation is essential in driving the development of the embryo, effectively telling each cell its destiny. Tags are wiped, reapplied and wiped again in a cycle of erasure and reprogramming as the baby grows and changes in the womb. Fascinatingly, there seems to be a difference in how tags are applied to DNA inherited from the father versus the mother. This may go some way towards explaining patterns of disease inheritance.
Delicious as all this science is, I have more selfish motives in looking up the research. How should I apply the data to my own parenting? What if I stuff
6
up? Will a moment of inattention lead inevitably to Sofia becoming an anxious adult? As I run to attend her waking cry, tell people to turn her away from TV screens, and buy books for her dad to read to her, I feel Sofia’s biological surveillance camera turned on me - every action tagged and recorded on her DNA.
There’s worse to come. Unfair as it may seem, my actions may affect not only Sofia, but her children as well.
Epigenetics is how the environment thumbprints an individual, allowing them to respond and adapt to changing conditions in their lifetime. Until recently, it was assumed that these adaptations died with the person. However, some elegant studies suggest that epigenetic tags may be passed down to future generations.
In the 1980s, a preventative-health specialist called Lars Olov Bygren started studying the population of Norrbotten, Sweden’s northernmost county, lying within the Arctic Circle. This extremely isolated population was particularly vulnerable to famine, punctuated by the odd year where harvests were so successful the inhabitants had to gorge themselves. Bygren found that parents who had gone from famine to feast in one season, had children who died earlier on average compared to those who had starved consistently. What was even more astonishing was that the grandchildren had even shorter lives - the effect magnified over generations to produce a whopping 32-year difference in lifespan.
7
Eminent New Zealand scientist Sir Peter Gluckman has proposed a theory to explain this and other findings. The Predictive Adaptive Response Theory holds that a foetus will adapt to an environment while in the womb, ‘predicting’ that it will find a similar environment once born. If there is a mismatch between these two environments, problems will arise. For example, a foetus which experiences poor nutrition in the womb will adapt its body to process foods efficiently and store energy quickly. When it is born into an environment of plenty, problems such as obesity, heart disease and diabetes will result.
How can we be sure that it is these conditions in the womb that lead to problems in adulthood? Are there points at which we can still change the final outcome? It is here that longitudinal studies – which follow a large group of subjects over a long period of time – come in useful. The Avon Longitudinal Study of Parents and Children (ALSPAC) surveyed children born to 14,000 mothers in the United Kingdom in the early 1990s. It found that boys whose fathers had started smoking just before puberty, in a period when the all-important sperm cells were starting to form, were more likely to be obese. This suggests that there are critical periods during which environment is more likely to influence outcome. Because the daughters of these fathers were not affected, it also suggests that epigenetic tags can be inherited differently by the sexes.
8
Longitudinal studies are a powerful, though expensive, tool in determining cause and effect and New Zealand has been a pioneer in this field. The Otago longitudinal study was one of the world’s first and over thirty years later, continues to produce valuable data. Growing Up in New Zealand is the newest in this venerable tradition, following 7,000 Kiwi families from before birth to adulthood. Epigenetics is a key focus of this new study.
If environment can impact on genes, is the reverse true? Without a doubt the rapid evolution of the human race – in technology and capability if not in genetic structure – has impacted on our planet. There does seem to be a certain symmetry to the idea that the environment can change how our genes operate and vice versa. We are all part of a continuous cycle, changing and evolving with one another. Things work well when all sides can keep pace.
If a human system is a microcosm of much larger systems around it, maybe there are also parallels in the ways they operate. Let’s do a thought experiment. A trauma of some sort – war, famine, a natural disaster – causes an epigenetic change in a population. It’s unknown how long epigenetic tags persist – perhaps only two generations, maybe more. For that period, the frame has shifted and there is physical and psychosocial change. But over time, given the right nurturing conditions, the scar slowly heals. Does our planet also have the ability to drift back towards normal? Does it, too have critical periods during which it is more vulnerable?
9
In any case, if the environment can tag our genes and these tags can be inherited by our descendants, it seems to be even more reason to ensure that our environment is as good as we can make it. Otherwise we may find that a permanent change to our planet leads to a permanent change in our species.
In 1769, the young James Cook was sent to Tahiti as part of a coordinated global effort to accurately observe the Transit of Venus. A skilled cartographer and mathematician, his measurements helped the leading scientists of the day to calculate the size of our solar system. The circumnavigation and mapping of New Zealand was a lucky by-product of this trip.
In 2012, I stand on the newly renovated Tolaga Bay Wharf in Gisborne, Aotearoa, peering into a specially modified telescope. The baby, yet to become Sofia, kicks within me. The tiny black speck of Venus crawls onto the surface of the sun. At the same time, citizens in Norrbotten look up at the midnight sun. Our goal this time is not measurement but participation, in an international and historical event.
In the 18th century, science was a beacon shining outwards, illuminating discoveries which led to political and industrial revolutions. In our 21st century, science has often looked inwards, patiently dissecting the minutiae of atoms or bodies in the knowledge that the tiniest building block can change the course of the world. In 1769, Cook navigated outer seas. In 2012, I navigate my inner sea on which a baby drifts gradually to sleep.
10
Bibliography
Bay J, Slobada D, Vickers M. Feast or Famine: Environment, Gene Expression and Evolution. LENScience Senior Biology Seminar Series. lens.auckland.ac.nz/images/b/bf/Feast_or_Famine_2009.pdf, accessed 26/9/12.
Bolatti V, Baccarelli A. Environmental Epigenetics (Review). Heredity (2010) 105, 105-112.
Green, H. Epigenetics (video/TV). Scishow, uploaded on Jan 22, 2012. www.youtube.com/watch?v=kp1bZEUgqVI
Cloud, J. Why Your DNA Isn't Your Destiny. Time Magazine, Wednesday, Jan. 06, 2010.
Goldberg A, Allis C, Bernstein E. Epigenetics: A Landscape Takes Shape. Cell 128, Feb 23, 2007 635-8.
Hunter P. Special report: What genes remember. Prospect Magazine, May 2008, issue 146.
11
Liggins Institute (website): Epigenetics. www.liggins.auckland.ac.nz/uoa/home/about/research-themes/developmentalepigenetics, accessed 25/9/12.
Liggins Institute (online news release): International study finds new link between mother’s pregnancy diet and offspring’s chances of obesity. www.liggins.auckland.ac.nz/uoa/home/news/template/news_item.jsp?cid=377329, accessed 25/9/12.
Morton, S et al. Report 1. Growing Up in New Zealand: Before we are born. Nov 2010. www.growingup.co.nz/research/results.aspx, accessed 25/9/12.
Vercelli, D. Genetics, epigenetics, and the environment: Switching, buffering, releasing. The Journal of Allergy and Clinical Immunology, Volume 113, Issue 3 , Pages 381-386, March 2004.
Vimpani, G. Child Health: Contexts, Consequences and Challenges. Royal Australasian College of Physicians News, June 2012, 8-10.
www.royalsociety.org.nz/media/EpigeneticsNavigatingOurInnerSeas_ReneeLiang_93.pdf
Renee Liang
Creative non-fiction
Science lets us see the way nature is; we experience this as we glimpse the workings of the same great celestial clock James Cook saw when the transit of Venus began at the predicted moment in June 1769. Science is the compass on the voyage we must all make into the twenty-first century. That we have it in our possession is astonishing. That we should never have found it, or that we should turn our back on it, is quite simply unthinkable.
Professor Sir Paul Callaghan (1947-2012)
It’s the middle of the night and I’m up once again for a feed. Sofia, a chubby 2-month-old bundle, smiles confidently up at me as she opens her mouth, but I’m too preoccupied until I remember and quickly smile back. Be present. Show your love.
It seems to be the lot of the modern parent that they’re constantly swimming in guilt. Am I eating the right diet to make good breastmilk? Are we stimulating, sleeping, burping her enough? As a researcher, I believe in science as a foundation for health. But as a mother, I find all this scientifically-validated advice restrictive – and, I’ll admit, a bit nannyish. From the moment I thought I might be pregnant, I’ve been bombarded with information on what (not) to eat, how to exercise, what to read. Midwives, Plunket nurses and Karitane
2
visitors invite themselves around. I have fridge magnets with phone numbers, free government-sponsored DVDs, and stacks of books next to my feeding chair. I don’t read them because Sofia looks at me and I smile – because I want to, not because of what the books say.
Is science really the compass that will help me guide my daughter to her brightest future? You only need listen to ‘helpful’ grandparents to work out that baby advice follows trends, like everything else. But with the explosion of research into early human development, that advice has snowballed. Epigenetics is emerging as potentially one of the most significant fields of study.
For over half a century it’s been known that a mutation – a tiny slip-up in the precise process of DNA transcription or copying – can lead to catastrophic disease. Mutations are also the process by which the human blueprint spontaneously changes, serendipitously adapting us to changing environments. Coupled with natural selection, these form the basis of evolution. Sadly, the individual in whom this takes place does not enjoy the benefits of being a freak. The process takes many generations. Unfortunately we live in an era where environmental change seems to ride an ever-steeper logarithmic curve. Traditional evolution won’t work in time to save us from ourselves.
However, there’s a little ray of light. The idea that we can adapt quickly to our environment, then pass on these attributes to our children, has long been poo-pooed by the establishment (ironically, led by one Charles Darwin.) It turns
3
out that Darwin’s great rival Lamarck, once consigned to history’s bin of discredited scientists, may well get the last laugh.
Epigenetics is a term first coined by developmental biologist Conrad Waddington in 1942 - interestingly, predating Watson and Crick’s 1953 elucidation of the structure of DNA. Epigenetics refers to the idea that an organism’s experience alters the expression of its genes. This happens through the application of ‘tags’ over (epi) the genetic blueprint. This affects the way DNA is then read. To use a simple metaphor: if nucleotide bases are an alphabet, genes the words and a strand of DNA a sentence, then epigenetic tags are the punctuation.
Since all cells in a body carry the same copy of DNA, something is required to tell each cell which bit of the DNA to use. There are codes and switches embedded in the DNA itself, but epigenetic tags act as a kind of external add-on.
Two types of tags have been identified to date. Methylation, the attachment of methyl chemical groups to certain points on the DNA blueprint, causes the reading machinery of the host cell to skip. This affects which proteins are manufactured and therefore how that cell functions – a process known as translation. Proteins called histones also change the reading of DNA by ‘spooling’ or winding the strands of genetic material. DNA must be unspooled in order to be translated. In effect, methylation tells the cell what to read, and
4
histones change the speed of reading. The underlying structure of the DNA remains unchanged.
What are some of the real-world consequences of epigenetic tagging? It’s early days, but already there are tantalizing clues. Canadian scientist Michael Meaney has recently shown that rat pups frequently groomed and licked by their mothers have a better response to stress as adults than rat pups who are cuddled less. Meaney has also shown that these differences are due to changes in gene expression.
So how does Meaney’s research translate to me in the real world? If my daughter misses out on a look or cuddle because I am too busy checking emails, will this lead to her being unable to cope in later life? Talk about motherly guilt!
Of course, it’s a long way from animal experiments to the complexities of human social interaction. As scientific papers are fond of pointing out, more data is needed. But it’s tempting to extrapolate. It’s long been observed, both anecdotally in and formal studies, that children deprived of physical or emotional nurture in early life respond more poorly to stress as adults. It’s also been assumed that the path from poor nurture to a misspent adulthood must be a complex web of many different factors. But what if (playing the devil’s advocate), it was just due to the vandalism of a few wrongly-tagged genes? Would modern medicine then be able to develop a quick fix, an anti-poverty pill? Governments the world over would breathe a sigh of relief.
5
This does seem to take the science too far, at least for now. But research on humans supports the idea that maternal behaviour is important. New Zealand scientists at the Liggins Institute, world leaders in the field of early human development, have discovered that how a mother eats during pregnancy – specifically during the first trimester - can affect the health of a foetus through its life. A child born to a mother with a poor diet is more likely to suffer from early puberty, eat more fatty foods, be less likely to exercise and suffer from heart disease, high blood pressure, diabetes and obesity. A child born to a mother with an overly rich diet fares even worse in terms of future disease.
The first thousand days, from conception to the second birthday, is known to be critical to a child’s development. It is in this period that crucial brain connections are made and cells differentiate into their specialized roles. This is also when the genetic blueprint is most susceptible to epigenetic tagging. Researchers have found that DNA methylation is essential in driving the development of the embryo, effectively telling each cell its destiny. Tags are wiped, reapplied and wiped again in a cycle of erasure and reprogramming as the baby grows and changes in the womb. Fascinatingly, there seems to be a difference in how tags are applied to DNA inherited from the father versus the mother. This may go some way towards explaining patterns of disease inheritance.
Delicious as all this science is, I have more selfish motives in looking up the research. How should I apply the data to my own parenting? What if I stuff
6
up? Will a moment of inattention lead inevitably to Sofia becoming an anxious adult? As I run to attend her waking cry, tell people to turn her away from TV screens, and buy books for her dad to read to her, I feel Sofia’s biological surveillance camera turned on me - every action tagged and recorded on her DNA.
There’s worse to come. Unfair as it may seem, my actions may affect not only Sofia, but her children as well.
Epigenetics is how the environment thumbprints an individual, allowing them to respond and adapt to changing conditions in their lifetime. Until recently, it was assumed that these adaptations died with the person. However, some elegant studies suggest that epigenetic tags may be passed down to future generations.
In the 1980s, a preventative-health specialist called Lars Olov Bygren started studying the population of Norrbotten, Sweden’s northernmost county, lying within the Arctic Circle. This extremely isolated population was particularly vulnerable to famine, punctuated by the odd year where harvests were so successful the inhabitants had to gorge themselves. Bygren found that parents who had gone from famine to feast in one season, had children who died earlier on average compared to those who had starved consistently. What was even more astonishing was that the grandchildren had even shorter lives - the effect magnified over generations to produce a whopping 32-year difference in lifespan.
7
Eminent New Zealand scientist Sir Peter Gluckman has proposed a theory to explain this and other findings. The Predictive Adaptive Response Theory holds that a foetus will adapt to an environment while in the womb, ‘predicting’ that it will find a similar environment once born. If there is a mismatch between these two environments, problems will arise. For example, a foetus which experiences poor nutrition in the womb will adapt its body to process foods efficiently and store energy quickly. When it is born into an environment of plenty, problems such as obesity, heart disease and diabetes will result.
How can we be sure that it is these conditions in the womb that lead to problems in adulthood? Are there points at which we can still change the final outcome? It is here that longitudinal studies – which follow a large group of subjects over a long period of time – come in useful. The Avon Longitudinal Study of Parents and Children (ALSPAC) surveyed children born to 14,000 mothers in the United Kingdom in the early 1990s. It found that boys whose fathers had started smoking just before puberty, in a period when the all-important sperm cells were starting to form, were more likely to be obese. This suggests that there are critical periods during which environment is more likely to influence outcome. Because the daughters of these fathers were not affected, it also suggests that epigenetic tags can be inherited differently by the sexes.
8
Longitudinal studies are a powerful, though expensive, tool in determining cause and effect and New Zealand has been a pioneer in this field. The Otago longitudinal study was one of the world’s first and over thirty years later, continues to produce valuable data. Growing Up in New Zealand is the newest in this venerable tradition, following 7,000 Kiwi families from before birth to adulthood. Epigenetics is a key focus of this new study.
If environment can impact on genes, is the reverse true? Without a doubt the rapid evolution of the human race – in technology and capability if not in genetic structure – has impacted on our planet. There does seem to be a certain symmetry to the idea that the environment can change how our genes operate and vice versa. We are all part of a continuous cycle, changing and evolving with one another. Things work well when all sides can keep pace.
If a human system is a microcosm of much larger systems around it, maybe there are also parallels in the ways they operate. Let’s do a thought experiment. A trauma of some sort – war, famine, a natural disaster – causes an epigenetic change in a population. It’s unknown how long epigenetic tags persist – perhaps only two generations, maybe more. For that period, the frame has shifted and there is physical and psychosocial change. But over time, given the right nurturing conditions, the scar slowly heals. Does our planet also have the ability to drift back towards normal? Does it, too have critical periods during which it is more vulnerable?
9
In any case, if the environment can tag our genes and these tags can be inherited by our descendants, it seems to be even more reason to ensure that our environment is as good as we can make it. Otherwise we may find that a permanent change to our planet leads to a permanent change in our species.
In 1769, the young James Cook was sent to Tahiti as part of a coordinated global effort to accurately observe the Transit of Venus. A skilled cartographer and mathematician, his measurements helped the leading scientists of the day to calculate the size of our solar system. The circumnavigation and mapping of New Zealand was a lucky by-product of this trip.
In 2012, I stand on the newly renovated Tolaga Bay Wharf in Gisborne, Aotearoa, peering into a specially modified telescope. The baby, yet to become Sofia, kicks within me. The tiny black speck of Venus crawls onto the surface of the sun. At the same time, citizens in Norrbotten look up at the midnight sun. Our goal this time is not measurement but participation, in an international and historical event.
In the 18th century, science was a beacon shining outwards, illuminating discoveries which led to political and industrial revolutions. In our 21st century, science has often looked inwards, patiently dissecting the minutiae of atoms or bodies in the knowledge that the tiniest building block can change the course of the world. In 1769, Cook navigated outer seas. In 2012, I navigate my inner sea on which a baby drifts gradually to sleep.
10
Bibliography
Bay J, Slobada D, Vickers M. Feast or Famine: Environment, Gene Expression and Evolution. LENScience Senior Biology Seminar Series. lens.auckland.ac.nz/images/b/bf/Feast_or_Famine_2009.pdf, accessed 26/9/12.
Bolatti V, Baccarelli A. Environmental Epigenetics (Review). Heredity (2010) 105, 105-112.
Green, H. Epigenetics (video/TV). Scishow, uploaded on Jan 22, 2012. www.youtube.com/watch?v=kp1bZEUgqVI
Cloud, J. Why Your DNA Isn't Your Destiny. Time Magazine, Wednesday, Jan. 06, 2010.
Goldberg A, Allis C, Bernstein E. Epigenetics: A Landscape Takes Shape. Cell 128, Feb 23, 2007 635-8.
Hunter P. Special report: What genes remember. Prospect Magazine, May 2008, issue 146.
11
Liggins Institute (website): Epigenetics. www.liggins.auckland.ac.nz/uoa/home/about/research-themes/developmentalepigenetics, accessed 25/9/12.
Liggins Institute (online news release): International study finds new link between mother’s pregnancy diet and offspring’s chances of obesity. www.liggins.auckland.ac.nz/uoa/home/news/template/news_item.jsp?cid=377329, accessed 25/9/12.
Morton, S et al. Report 1. Growing Up in New Zealand: Before we are born. Nov 2010. www.growingup.co.nz/research/results.aspx, accessed 25/9/12.
Vercelli, D. Genetics, epigenetics, and the environment: Switching, buffering, releasing. The Journal of Allergy and Clinical Immunology, Volume 113, Issue 3 , Pages 381-386, March 2004.
Vimpani, G. Child Health: Contexts, Consequences and Challenges. Royal Australasian College of Physicians News, June 2012, 8-10.
www.royalsociety.org.nz/media/EpigeneticsNavigatingOurInnerSeas_ReneeLiang_93.pdf