> http://www.newscientist.com/channel/life/mg19926641.500-rewriting-dar...
> Rewriting Darwin: The new non-genetic inheritance
> 09 July 2008
> From New Scientist Print Edition. Subscribe and get 4 free issues.
> Emma Young
>
>  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).
>
> “All female honeybees, including queens, develop from genetically identical larvae”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.
>
> The legacy of stress
> Diet is not the only environmental factor that can influence the epigenetic setting of some genes. Michael Meaney at McGill
> University in Montreal, Canada, and colleagues have found that newborn mice neglected by their mothers are more fearful in adulthood
> - and that these mice show much higher than normal levels of methylation of certain genes involved in the stress response. On a
> brighter note, these mice also point the way to a possible way to reverse epigenetic changes (see "In sickness and in health").
>
> In humans, too, there are troubling hints that damaging experiences early in life, while the brain is still developing, can affect
> epigenetic settings, perhaps with catastrophic consequences. In May, Meaney and his colleagues reported a study of 13 men who had
> committed suicide, all of whom had been victims of child abuse. They showed clear epigenetic differences in their brains, compared
> with the brains of men who had died of other causes. It is possible that the changes in epigenetic marks were caused by the exposure
> to childhood abuse, says the team. Could the changes have contributed to their suicides too?
>
> There is recent evidence that abnormal epigenetic patterns play a role in mental health disorders. In March, Arturas Petronis at the
> Centre for Addiction and Mental Health in Toronto, Canada, and colleagues reported the first epigenome-wide scan of post-mortem
> brain tissue from 35 people who had suffered from schizophrenia. They found a distinctive epigenetic pattern, controlling the
> expression of roughly 40 genes (The American Journal of Human Genetics, vol 82, p 696). Several of the genes were related to
> neurotransmitters, to brain development and to other processes linked to schizophrenia. These findings lay the groundwork for a new
> way of understanding mental illness, says Petronis, as a disease with a significant epigenetic component.
>
> “These findings lay the groundwork for a new way of understanding mental illness”As with the people who had committed suicide in
> Meaney's study, these epigenetic marks may have arisen during development. Yet there are also hints that the people with
> schizophrenia might instead have inherited them from their parents - and that they in turn might pass the marks on to their own
> children. In theory, epigenetic marks are wiped clear between generations in mammals. Intriguingly, though, the abnormalities in DNA
> methylation in Petronis's subjects were not restricted to their frontal cortex: they were also present in their sperm. "[This]
> suggests that it is possible that inherited epigenetic abnormalities may be contributing to the familial nature of schizophrenia and
> bipolar disorder," says team member Jonathan Mill at the Institute of Psychiatry at King's College London.
>
> This work is only suggestive, but when it comes to cancer, the evidence is stronger. Some colorectal cancers are known to develop
> when a key DNA-repair gene called MHL1 becomes coated in methyl groups, preventing it from working. In 2007, Ward and her colleagues
> published a study of a woman with this type of cancer and her three children. The MHL1 gene was active in two of the children, but
> one son had a heavily methylated, silenced gene like his mother (The New England Journal of Medicine, vol 356, p 697).
>
> The paper caused a sensation among cancer researchers because it suggested an entirely new way in which disease risk might be
> inherited. Of course the finding could have been a coincidence, or the son might have inherited a genetic propensity to methylation
> of this gene, rather than the epigenetic mark itself. Since the paper came out, though, direct inheritance is starting to look more
> likely. Other teams have identified similar families, and in all cases the effect seems to be transmitted down the maternal line via
> the egg. The MHL1 gene in the sperm of affected men appears normal.
>
> Some epigenetic marks may also be inherited from fathers, however. In a now classic study published in 2005, Matthew Anway at the
> University of Idaho in Moscow and colleagues showed that male rats exposed to the common crop fungicide vinclozolin in the womb were
> less fertile and had a higher than normal risk of developing cancer and kidney defects. Not only were these effects transmitted to
> their offspring, they were passed from father to son through the three following generations as well (Science, vol 308, p 1466). The
> team found no DNA changes, only altered DNA methylation patterns in the sperm of these rats, suggesting that epigenetic factors were
> to blame.
>
> The following year, a team at the University of Maryland in Baltimore found that male mice that had inhaled cocaine passed memory
> problems onto their pups. Again, their sperm showed no apparent DNA damage, but in the seminiferous tubules, where sperm are
> produced, the researchers found changes in the levels of two enzymes involved in methylating DNA.
>
> In people, too, there is evidence that environmental impacts on fathers and mothers can produce changes in their children. This has
> led some researchers to consider a startling possibility. Could the current epidemic of type II diabetes and obesity in developed
> countries be related to what our parents and our grandparents ate?
>
> “Could the current epidemic of obesity be related to what our parents and grandparents ate?”Nutrition does seem to have some lasting
> effect, according to a study by Marcus Pembrey of the Institute of Child Health at University College London and his colleagues.
> They analysed records from the isolated community of Överkalix in northern Sweden and found that men whose paternal grandfathers had
> suffered a shortage of food between the ages of 9 and 12 lived longer than their peers (European Journal of Human Genetics, vol 14,
> p 159). A similar maternal-line effect existed for women, but in this case by far the biggest effect on longevity of the
> granddaughters occurred when food was limited while grandmothers were in the womb or were infants. It would appear that humans
> thrive on relatively meagre rations, and the team concluded that under these conditions some sort of key information - perhaps
> epigenetic in nature - was being captured at the crucial stages of sperm and egg formation, then passed down generations.
>
> Pembrey's team also looked at more recent records from the UK, collected for the Avon Longitudinal Study of Parents and Children.
> They identified 166 fathers who reported starting smoking before the age of 11 and found that their sons - but not their daughters -
> had a significantly higher than average body mass index at the age of 9.
>
> Also in 2006, Tony Hsiu-Hsi Chen at the National Taiwan University in Taipei and colleagues reported that the offspring of men who
> regularly chewed betel nuts had twice the normal risk of developing metabolic syndrome during childhood. Betel nuts are also
> associated with several symptoms of metabolic syndrome in chewers including increased heart rate, blood pressure, waist size and
> body weight.
>
> The mother's nutrition might affect a child's risk of obesity, too. Women in the Netherlands who were in the first two trimesters of
> pregnancy during a famine in 1944 and 1945 gave birth to boys who, at 19, were much more likely to be obese.
>
> All these results raise an important question. Why should factors like food intake or smoking around the time sperm or eggs are
> created, or at the embryo stage, have such an influence on a child's metabolism and weight?
>
> Extended periods of too much or too little food might trigger a switch to a pattern of gene expression that results in earlier
> puberty and so earlier mortality, says Pembrey - and this might be heritable. "The reason why some people gain weight more easily is
> because their metabolic genes are used differently," says Reinhard Stöeger at the University of Washington in Seattle. He suggests
> that long before the emergence of modern humans, a network of metabolic genes evolved that was honed for a relative scarcity of
> food, but not feast or famine. "These genes have become epigenetically programmed during the early stages of life in response to
> adverse environmental conditions - such as feast. This might explain the current epidemic of type II diabetes and obesity in the
> west, where food is plentiful." Prolonged epigenetic silencing in response to the environment might also lead to a DNA change that
> "locks in" epigenetic marks, Stöeger suggests.
>
> Out of the melting pot of recent findings, a host of fundamental questions are now being thrown up. If what we eat could affect our
> grandchildren, should we be more careful? If so, in what ways? Should we be more concerned about the long-term impact of war or
> child abuse? Could we choose a diet to reduce our own cancer risk, and that of our children? We are only starting to get an inkling
> about how to answer these, but one thing is clear: genes are only part of the story.
>
> Evolution - Learn more about the struggle to survive in our comprehensive special report.
>
> Genetics - Keep up with the pace in our continually updated special report.
>
> From issue 2664 of New Scientist magazine, 09 July 2008, page 28-33
> 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.
>
> --
> Frederick Martin McNeill
> Poway, California, United States of America
> mmcne...@fuzzysys.com
> ******************************************
> "To see what is in front of one's nose needs a constant struggle."
> - George Orwell
> ******************************************