Rewriting Darwin: The new non-genetic inheritance
Confutius
* 09 July 2008
* From New Scientist
* 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.