Rosa Lichtenstein
10th July 2008, 13:58
Looks like scientists are about to change their minds, yet again:
Rewriting Darwin: The new non-genetic inheritance
HALF a century before Charles Darwin published On the Origin of Species, the French naturalist Jean-Baptiste Lamarck outlined his own theory of evolution. A cornerstone of this was the idea that characteristics acquired during an individual's lifetime can be passed on to their offspring. In its day, Lamarck's theory was generally ignored or lampooned. Then came Darwin, and Gregor Mendel's discovery of genetics. In recent years, ideas along the lines of Richard Dawkins's concept of the "selfish gene" have come to dominate discussions about heritability, and with the exception of a brief surge of interest in the late 19th and early 20th centuries, "Lamarckism" has long been consigned to the theory junkyard.
Now all that is changing. No one is arguing that Lamarck got everything right, but over the past decade it has become increasingly clear that environmental factors, such as diet or stress, can have biological consequences that are transmitted to offspring without a single change to gene sequences taking place. In fact, some biologists are already starting to consider this process as routine. However, fully accepting the idea, provocatively dubbed the "new Lamarckism", would mean a radical rewrite of modern evolutionary theory. Not surprisingly, there are some who see that as heresy. "It means the demise of the selfish-gene theory," says Eva Jablonka at Tel Aviv University, Israel. "The whole discourse about heredity and evolution will change" (see "Rewriting Darwin and Dawkins?").
That's not all. The implications for public health could also be immense. Some researchers are talking about a paradigm shift in understanding the causes of disease. For example, non-genetic inheritance might help explain the current obesity epidemic, or why there are family patterns for certain cancers and other disorders, but no discernible genetic cause. "It's a whole new way of looking at the inheritance and causes of various diseases, including schizophrenia, bipolar disorder and diabetes, as well as cancer," says Robyn Ward of the cancer research centre at the University of New South Wales in Sydney, Australia.
Lamarck's ideas about exactly how non-genetic inheritance might work were woolly at best. He wrote, for example, of the giraffe's neck becoming elongated over generations because of the animal's habit of stretching up to feed on leaves in high treetops. The recent research, by contrast, has a firm basis in biological mechanisms - in so-called "epigenetic" change.
Epigenetics deals with how gene activity is regulated within a cell - which genes are switched on or off, which are dimmed and how, and when all this happens. For instance, while the cells in the liver and skin of an individual contain exactly the same DNA, their specific epigenetic settings mean the tissues look very different and do a totally different job. Likewise, different genes may be expressed in the same tissue at different stages of development and throughout life. Researchers are a long way from knowing exactly what mechanisms control all this, but they have made some headway.
Inside the nucleus, DNA is packaged around bundles of proteins called histones, which have tails that stick out from the core. One factor that affects gene expression is the pattern of chemical modifications to these tails, such as the presence or absence of acetyl and methyl groups. Genes can also be silenced directly via enzymes that bind methyl groups onto the DNA. The so-called RNA interference (RNAi) system can direct this activity, via small RNA strands. As well as controlling DNA methylation and modifying histones, these RNAi molecules target messenger RNA - much longer strands that act as intermediaries between DNA sequences and the proteins they code for. By breaking mRNA down into small segments, the RNAi molecules ensure that a certain gene cannot be translated into its protein. In short, RNAi creates the epigenetic "marks" that control the activity of genes.
We know that genes - and possibly also non-coding DNA - control RNAi and so are involved in determining an individual's epigenetic settings. It is becoming increasingly apparent, though, that environmental factors can have a direct impact too, with potentially life-changing implications. The clearest example of this comes from honeybees. All female honeybees develop from genetically identical larvae, but those fed on royal jelly become fertile queens while the rest are doomed to life as sterile workers. In March this year, an Australian team led by Ryszard Maleszka at the Australian National University in Canberra showed that epigenetic mechanisms account for this. They used RNAi to silence a gene for DNA methyltransferase - an enzyme necessary for adding methyl groups to DNA - in honeybee larvae. Most of these larvae emerged as queens, without ever having tasted royal jelly (Science, DOI: 10.1126/science.1153069).
For honeybees then, what they eat during early development creates an epigenetic setting that has fundamental lifelong implications. This is an extreme example, but researchers are starting to realise that similar mechanisms are at play in other animals, and even in humans. And, as for honeybees, it seems there is a critical early period during which an individual's pattern of gene expression is "programmed" to a large extent. Environmental factors can feed into this programming, possibly with long-term health impacts.
In 2000, Randy Jirtle at Duke University in Durham, North Carolina, led a ground-breaking experiment on a strain of genetically identical mice. These mice carried the agouti gene, which makes them fat and prone to diabetes and cancer. Jirtle and his student Robert Waterland gave one group of females a diet rich in methyl groups before conception and during pregnancy. They found that the offspring were very different to their parents - they were slim and lived to a ripe old age. Though the pups had inherited the damaging agouti gene, the methyl groups had attached to the gene and dimmed its expression.
Jirtle then tried supplementing the diets of pregnant agouti mice with genistein, an oestrogen-like chemical found in soya. The dose was designed to be comparable to the amount consumed by a person on a high-soya diet, which is associated with a reduced risk of cancer and less body fat. These mice were also more likely to give birth to slim, healthy offspring which had less chance of becoming obese in adulthood. This change was associated with increased methylation of six DNA base-pair sites involved in regulating activity of the agouti gene.
These and other animal studies strongly suggest that a pregnant woman's diet can affect her child's epigenetic marks. So perhaps it is not surprising that the effect of certain nutrients is being called into question. Folate, for example, is a potent methyl donor. It is routinely recommended during pregnancy and added to cereal products in certain countries, including the US, because it reduces the risk of spinal tube defects if eaten around the time of conception. But Jirtle wonders whether it could also be inducing as-yet-unknown, damaging epigenetic effects....
Rewriting Darwin and Dawkins?
The realisation that individuals can acquire characteristics through interaction with their environment and then pass these on to their offspring may force us to rethink evolutionary theory. While examples of this "transgenerational epigenetic inheritance" are only just emerging in mammals, there is long-standing and widespread evidence for it in plants and fungi. That may explain why botanists are much more ready to acknowledge and promote the idea that epigenetic inheritance has a significant role in evolution, whereas zoologists are generally reluctant to do so, says Eva Jablonka from Tel Aviv University, Israel.
That looks set to change. "There was a trickle of findings of epigenetic inheritance in animals through the 20th century, and it is turning into a flood about now," says Russell Bonduriansky, at the University of New South Wales in Sydney, Australia. One of his favourite recent examples involves the water flea, daphnia. When predators are around, the fleas develop large, defensive spines. If they then reproduce, their offspring also develop these spines - even when not exposed to predators.
For Bonduriansky, this suggests a possible adaptive function of epigenetic inheritance - the fine-tuning of an individual to short-term variations in its environment. "There's no lag time for the offspring to respond to the environment on their own," he says.
The idea that epigenetic variation could be adaptive - rather than a form of random, non-directed variation - is very controversial, harking back as it does to the discredited theory of Lamarckian evolution. Nevertheless, this has not deterred some researchers from exploring the full implications of epigenetic inheritance.
For example, there is evidence that epigenetic changes can affect mate preference. Last year, David Crews and Andrea Gore at the University of Texas at Austin published a study of male rats whose great-grandfathers had been exposed to the fungicide vinclozalin. Previous research has revealed that such exposure leads to increased infertility and higher risks of cancer even four generations later. Crews and Gore found that female rats tended to avoid these males. They could sense something was wrong, says Gore. The females seemed to select mates on the basis of an epigenetic pattern, as opposed to a genetic difference, she adds.
Back to the future
For Bonduriansky the accumulating evidence calls for a radical rethink of how evolution works. Jablonka, too, believes that "Lamarckian" mechanisms should now be integrated into evolutionary theory, which should focus on mechanisms, rather than units, of inheritance. "This would be very significant," she says. "It would reintroduce development, in a very direct and strong sense, into heredity and hence evolution. It would mean the pre-synthesis view of evolution, which was very diverse and very rich, can return, but with molecular mechanisms attached."
That needn't necessarily mean an end to the idea of the gene as the basic unit of inheritance, or Richard Dawkins's selfish gene, according to some. "I don't think it violates the basic concept that Dawkins articulated," says Eric Richards, at Washington University in St Louis, Missouri. "Epigenetic marks can also be viewed as part of that basic unit in a more inclusive definition of a gene," he says.
What does Dawkins himself think? "The 'transgenerational' effects now being described are mildly interesting, but they cast no doubt whatsoever on the theory of the selfish gene," he says. He suggests, though, that the word "gene" should be replaced with "replicator". This selfish replicator, acting as the unit of selection, does not have to be a gene, but it does have to be replicated accurately, the occasional mutation aside. "Whether [epigenetic marks] will eventually be deemed to qualify as 'selfish replicators' will depend upon whether they are genuinely high-fidelity replicators with the capacity to go on for ever. This is important because otherwise there will be no interesting differences between those that are successful in natural selection and those that are not." If all the effects fade out within the first few generations, they cannot be said to be positively selected, Dawkins points out.
In sickness and in health
Epigenetic abnormalities have been found in nearly every type of cancer and in other diseases, such as cardiovascular disease. But the discovery that diseases can be caused by environmental factors influencing the expression of genes has an upside. "The beauty of any epigenetic modification is that it is reversible by drugs," says Robyn Ward from the University of New South Wales in Sydney, Australia.
Take the epigenetic marks acquired by mice as a result of maternal neglect during infancy. Here, methyl groups become attached to genes involved in the stress response, resulting in heightened anxiety. But, using drugs, Michael Meaney at McGill University in Montreal, Canada, and his team have reversed the methylation of these genes and their associated behavioural responses in adulthood (Journal of Neuroscience, vol 25, p 11045). They injected the drugs directly into the brain although it is possible that a special diet could do the same trick, Meaney says.
NEW ROLE FOR OLD DRUGS
Other drugs that influence methylation are now in early-stage anti-cancer trials. Some of them are not new, but are being reassessed in the light of new knowledge about how they work. Azacytidine, for example, which was used years ago with limited success to treat a range of bone-marrow stem-cell disorders, is undergoing trials again on these very same disorders. Now that it has become clear the drug induces epigenetic changes, researchers are altering doses and redesigning trials with the aim of activating tumour-suppressor genes that have been silenced by methylation.
This approach does have a major drawback - epigenetic drugs are not specific. Side effects, such as nausea and diarrhoea, are probably down to their broad range of action, says Ward. It might be possible to target drugs more specifically, but that is a very long way off. Still, the fact that it offers a whole new way of treating disease leads many to consider the epigenetics approach to be very promising.
From the New Scientist 09/07/08
http://www.newscientist.com/channel/life/mg19926641.500-rewriting-darwin-the-new-nongenetic-inheritance.html
Rewriting Darwin: The new non-genetic inheritance
HALF a century before Charles Darwin published On the Origin of Species, the French naturalist Jean-Baptiste Lamarck outlined his own theory of evolution. A cornerstone of this was the idea that characteristics acquired during an individual's lifetime can be passed on to their offspring. In its day, Lamarck's theory was generally ignored or lampooned. Then came Darwin, and Gregor Mendel's discovery of genetics. In recent years, ideas along the lines of Richard Dawkins's concept of the "selfish gene" have come to dominate discussions about heritability, and with the exception of a brief surge of interest in the late 19th and early 20th centuries, "Lamarckism" has long been consigned to the theory junkyard.
Now all that is changing. No one is arguing that Lamarck got everything right, but over the past decade it has become increasingly clear that environmental factors, such as diet or stress, can have biological consequences that are transmitted to offspring without a single change to gene sequences taking place. In fact, some biologists are already starting to consider this process as routine. However, fully accepting the idea, provocatively dubbed the "new Lamarckism", would mean a radical rewrite of modern evolutionary theory. Not surprisingly, there are some who see that as heresy. "It means the demise of the selfish-gene theory," says Eva Jablonka at Tel Aviv University, Israel. "The whole discourse about heredity and evolution will change" (see "Rewriting Darwin and Dawkins?").
That's not all. The implications for public health could also be immense. Some researchers are talking about a paradigm shift in understanding the causes of disease. For example, non-genetic inheritance might help explain the current obesity epidemic, or why there are family patterns for certain cancers and other disorders, but no discernible genetic cause. "It's a whole new way of looking at the inheritance and causes of various diseases, including schizophrenia, bipolar disorder and diabetes, as well as cancer," says Robyn Ward of the cancer research centre at the University of New South Wales in Sydney, Australia.
Lamarck's ideas about exactly how non-genetic inheritance might work were woolly at best. He wrote, for example, of the giraffe's neck becoming elongated over generations because of the animal's habit of stretching up to feed on leaves in high treetops. The recent research, by contrast, has a firm basis in biological mechanisms - in so-called "epigenetic" change.
Epigenetics deals with how gene activity is regulated within a cell - which genes are switched on or off, which are dimmed and how, and when all this happens. For instance, while the cells in the liver and skin of an individual contain exactly the same DNA, their specific epigenetic settings mean the tissues look very different and do a totally different job. Likewise, different genes may be expressed in the same tissue at different stages of development and throughout life. Researchers are a long way from knowing exactly what mechanisms control all this, but they have made some headway.
Inside the nucleus, DNA is packaged around bundles of proteins called histones, which have tails that stick out from the core. One factor that affects gene expression is the pattern of chemical modifications to these tails, such as the presence or absence of acetyl and methyl groups. Genes can also be silenced directly via enzymes that bind methyl groups onto the DNA. The so-called RNA interference (RNAi) system can direct this activity, via small RNA strands. As well as controlling DNA methylation and modifying histones, these RNAi molecules target messenger RNA - much longer strands that act as intermediaries between DNA sequences and the proteins they code for. By breaking mRNA down into small segments, the RNAi molecules ensure that a certain gene cannot be translated into its protein. In short, RNAi creates the epigenetic "marks" that control the activity of genes.
We know that genes - and possibly also non-coding DNA - control RNAi and so are involved in determining an individual's epigenetic settings. It is becoming increasingly apparent, though, that environmental factors can have a direct impact too, with potentially life-changing implications. The clearest example of this comes from honeybees. All female honeybees develop from genetically identical larvae, but those fed on royal jelly become fertile queens while the rest are doomed to life as sterile workers. In March this year, an Australian team led by Ryszard Maleszka at the Australian National University in Canberra showed that epigenetic mechanisms account for this. They used RNAi to silence a gene for DNA methyltransferase - an enzyme necessary for adding methyl groups to DNA - in honeybee larvae. Most of these larvae emerged as queens, without ever having tasted royal jelly (Science, DOI: 10.1126/science.1153069).
For honeybees then, what they eat during early development creates an epigenetic setting that has fundamental lifelong implications. This is an extreme example, but researchers are starting to realise that similar mechanisms are at play in other animals, and even in humans. And, as for honeybees, it seems there is a critical early period during which an individual's pattern of gene expression is "programmed" to a large extent. Environmental factors can feed into this programming, possibly with long-term health impacts.
In 2000, Randy Jirtle at Duke University in Durham, North Carolina, led a ground-breaking experiment on a strain of genetically identical mice. These mice carried the agouti gene, which makes them fat and prone to diabetes and cancer. Jirtle and his student Robert Waterland gave one group of females a diet rich in methyl groups before conception and during pregnancy. They found that the offspring were very different to their parents - they were slim and lived to a ripe old age. Though the pups had inherited the damaging agouti gene, the methyl groups had attached to the gene and dimmed its expression.
Jirtle then tried supplementing the diets of pregnant agouti mice with genistein, an oestrogen-like chemical found in soya. The dose was designed to be comparable to the amount consumed by a person on a high-soya diet, which is associated with a reduced risk of cancer and less body fat. These mice were also more likely to give birth to slim, healthy offspring which had less chance of becoming obese in adulthood. This change was associated with increased methylation of six DNA base-pair sites involved in regulating activity of the agouti gene.
These and other animal studies strongly suggest that a pregnant woman's diet can affect her child's epigenetic marks. So perhaps it is not surprising that the effect of certain nutrients is being called into question. Folate, for example, is a potent methyl donor. It is routinely recommended during pregnancy and added to cereal products in certain countries, including the US, because it reduces the risk of spinal tube defects if eaten around the time of conception. But Jirtle wonders whether it could also be inducing as-yet-unknown, damaging epigenetic effects....
Rewriting Darwin and Dawkins?
The realisation that individuals can acquire characteristics through interaction with their environment and then pass these on to their offspring may force us to rethink evolutionary theory. While examples of this "transgenerational epigenetic inheritance" are only just emerging in mammals, there is long-standing and widespread evidence for it in plants and fungi. That may explain why botanists are much more ready to acknowledge and promote the idea that epigenetic inheritance has a significant role in evolution, whereas zoologists are generally reluctant to do so, says Eva Jablonka from Tel Aviv University, Israel.
That looks set to change. "There was a trickle of findings of epigenetic inheritance in animals through the 20th century, and it is turning into a flood about now," says Russell Bonduriansky, at the University of New South Wales in Sydney, Australia. One of his favourite recent examples involves the water flea, daphnia. When predators are around, the fleas develop large, defensive spines. If they then reproduce, their offspring also develop these spines - even when not exposed to predators.
For Bonduriansky, this suggests a possible adaptive function of epigenetic inheritance - the fine-tuning of an individual to short-term variations in its environment. "There's no lag time for the offspring to respond to the environment on their own," he says.
The idea that epigenetic variation could be adaptive - rather than a form of random, non-directed variation - is very controversial, harking back as it does to the discredited theory of Lamarckian evolution. Nevertheless, this has not deterred some researchers from exploring the full implications of epigenetic inheritance.
For example, there is evidence that epigenetic changes can affect mate preference. Last year, David Crews and Andrea Gore at the University of Texas at Austin published a study of male rats whose great-grandfathers had been exposed to the fungicide vinclozalin. Previous research has revealed that such exposure leads to increased infertility and higher risks of cancer even four generations later. Crews and Gore found that female rats tended to avoid these males. They could sense something was wrong, says Gore. The females seemed to select mates on the basis of an epigenetic pattern, as opposed to a genetic difference, she adds.
Back to the future
For Bonduriansky the accumulating evidence calls for a radical rethink of how evolution works. Jablonka, too, believes that "Lamarckian" mechanisms should now be integrated into evolutionary theory, which should focus on mechanisms, rather than units, of inheritance. "This would be very significant," she says. "It would reintroduce development, in a very direct and strong sense, into heredity and hence evolution. It would mean the pre-synthesis view of evolution, which was very diverse and very rich, can return, but with molecular mechanisms attached."
That needn't necessarily mean an end to the idea of the gene as the basic unit of inheritance, or Richard Dawkins's selfish gene, according to some. "I don't think it violates the basic concept that Dawkins articulated," says Eric Richards, at Washington University in St Louis, Missouri. "Epigenetic marks can also be viewed as part of that basic unit in a more inclusive definition of a gene," he says.
What does Dawkins himself think? "The 'transgenerational' effects now being described are mildly interesting, but they cast no doubt whatsoever on the theory of the selfish gene," he says. He suggests, though, that the word "gene" should be replaced with "replicator". This selfish replicator, acting as the unit of selection, does not have to be a gene, but it does have to be replicated accurately, the occasional mutation aside. "Whether [epigenetic marks] will eventually be deemed to qualify as 'selfish replicators' will depend upon whether they are genuinely high-fidelity replicators with the capacity to go on for ever. This is important because otherwise there will be no interesting differences between those that are successful in natural selection and those that are not." If all the effects fade out within the first few generations, they cannot be said to be positively selected, Dawkins points out.
In sickness and in health
Epigenetic abnormalities have been found in nearly every type of cancer and in other diseases, such as cardiovascular disease. But the discovery that diseases can be caused by environmental factors influencing the expression of genes has an upside. "The beauty of any epigenetic modification is that it is reversible by drugs," says Robyn Ward from the University of New South Wales in Sydney, Australia.
Take the epigenetic marks acquired by mice as a result of maternal neglect during infancy. Here, methyl groups become attached to genes involved in the stress response, resulting in heightened anxiety. But, using drugs, Michael Meaney at McGill University in Montreal, Canada, and his team have reversed the methylation of these genes and their associated behavioural responses in adulthood (Journal of Neuroscience, vol 25, p 11045). They injected the drugs directly into the brain although it is possible that a special diet could do the same trick, Meaney says.
NEW ROLE FOR OLD DRUGS
Other drugs that influence methylation are now in early-stage anti-cancer trials. Some of them are not new, but are being reassessed in the light of new knowledge about how they work. Azacytidine, for example, which was used years ago with limited success to treat a range of bone-marrow stem-cell disorders, is undergoing trials again on these very same disorders. Now that it has become clear the drug induces epigenetic changes, researchers are altering doses and redesigning trials with the aim of activating tumour-suppressor genes that have been silenced by methylation.
This approach does have a major drawback - epigenetic drugs are not specific. Side effects, such as nausea and diarrhoea, are probably down to their broad range of action, says Ward. It might be possible to target drugs more specifically, but that is a very long way off. Still, the fact that it offers a whole new way of treating disease leads many to consider the epigenetics approach to be very promising.
From the New Scientist 09/07/08
http://www.newscientist.com/channel/life/mg19926641.500-rewriting-darwin-the-new-nongenetic-inheritance.html