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DNA: it’s not destiny

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The whole of modern medicine rests upon the notion that, to a great extent,
your health is out of your control. Most biologists and doctors believe that
the functioning and health of any organism are largely due to DNA, the
coiled double helix of genetic coding within the nucleus engine-room that
holds the blueprint of the body’s proteins and amino acids.
DNA (deoxyribonucleic acid) is considered the architect, master builder and
central power station that builds the body and spearheads all of its dynamic
activities by selectively turning certain genes off or on.
DNA nucleotides, or genetic instructions, select certain RNA (ribonucleic
acid) molecules that, in turn, select from a large alphabet of amino acids
the genetic ‘words’ that make up specific proteins.
In the view of neo-Darwinists such as Richard Dawkins, our genes not only
possess the total power to control every aspect of our lives-with the rest
of the body simply the vehicle of transport-but they are also the harbingers
of a prepro-grammed future. We are only as healthy as our family history and
the genetic hand we’ve been dealt.
In the simplest terms, according to this view, genetics is destiny.
Nevertheless, a growing body of evidence refutes the idea that your future
health and likelihood of developing disease rests entirely with your genes.
In fact, scientists have begun to show that genes, far from being a
blueprint, are simply a potential path that we may follow-or not-depending
on our life circum-stances and environment.

Breast cancer and DNA

Most doctors believe that women with a family history of cancer are far more
likely to develop breast cancer themselves. Indeed, in the past, doctors
have even encouraged women in this situation who have yet to develop the
disease to undergo a mastectomy as a preemptive strike.
The 15-year US Women’s Health Initiative (WHI) study, which intended to
examine the benefits and safety of hormone replacement therapy (HRT) in more
than 16,000 women, was halted after only five years when scientists found
that women taking HRT were more likely to develop breast cancer, ovarian
cancer, stroke and heart disease.
When epidemiologists at the University of Rochester Medical Center
followed-up the women taking part in the WHI study who went on to develop
breast cancer, they assumed that they would find a higher incidence of
cancer among those who had a family history of the disease. However, this
was not the case. The evidence showed that whether or not a woman developed
cancer had only to do with whether she took HRT, not whether her family
members had cancer (Epidemiology, 2009; 20: 752-6).
According to new findings, outside influences, such as our diet or
environment, can alter our genes. Swedish researchers from the Karolinska
Institute in Sweden have discovered that DNA isolated from the muscles of
type 2 diabetics carry certain distinctive chemical marks on the gene
responsible for controlling the amount of fuel-either fat or sugars-burned
by the body’s cells (Cell Metabolism, 2009; 10: 189-98).
These same chemical marks, which aren’t present in healthy people, have also
been found in those with pre-diabetes. This suggests that the development of
diabetes is a process that begins with an aberration in the genes
responsible for processing sugar, and that this process is then triggered
and developed by outside influences or insults to the body.
This is not a new idea-only an idea whose time has finally come (see box,
page 8) through a new science called ‘epigenetics’: the study of how the
environment affects genes.

An open-door policy

The cytoplasm, or blob of jelly that makes up every cell in your body, is
encased in a semipermeable cell membrane, a triple layer of fat-like
molecules containing a variety of protein molecules that act like tiny
revolving doors that allow other molecules to either enter or exit the cell.

This means that whether or not a molecule gets through either partially or
totally is entirely at the discretion of the cell membrane. Some of these
gatekeeper proteins are called ‘receptors’, as they pick up external signals
from other molecules.
Although science still adheres to the notion that a cell is controlled by
its nucleus, researchers are now realizing that it’s the outside influ-ences
filtering through the cellular membrane that, in fact, control the cell and,
consequently, the behaviour and health of the entire organism.
As the father of epigenetics-Jean-Baptiste Lamarck-and others were aware
(see box below), a cell itself is simply a potential. Stripped down to its
basics without a membrane, the cells of any person-or animal-are
indistinguishable from those of any others. Every cell is ultimately only
made unique by the ‘information’ that is allowed in through its membrane. As
biologist Bruce Lipton puts it, the real brain of a cell is its membrane.
The membrane contains hundreds of thousands of protein receptor switches,
which possess the ability to regulate a cell’s function by turning a certain
gene on or off. However, what prompts the turn of the switch is an
environmental signal, so the true controller of a gene-whether it is
activated or not-is determined by any of the numerous influences that are
external to the body. This, in turn, affects the chemical coating, or
methylation, of the DNA double helix, which is exquisitely sensitive to the
environment, particularly in the early stages of life.

Fat-cat mice

Perhaps the best-known study to examine outside influences on the cell is
the recent research at Duke University on agouti mice. Mice with the agouti
gene are destined to be couch potatoes. The gene makes their fur
peach-coloured, and they are often hugely obese, with a tendency to develop
diabetes and cancer.
However, as the intervention in these studies, the pregnant agouti mice were
given vitamin B12, folic acid, choline and betaine, the need for all of
which is higher in animals with this genetic defect.
The result was that the offspring of the mothers that had received the
‘enriched’ diet were not only slim and brown but, unlike their mother, lived
out a normal lifespan (Mol Cell Biol, 2003; 23: 5293-300). External
influences such as dietary supplements dramatically overrode the offspring’s
genetic destiny by turning the agouti gene expression to ‘off’ .
As biologist Randy Jirtle, director of the Epigenetics and Imprinting
Laboratory at Duke, announced when the study was published, “This is where
environment interfaces with genomics”.
In humans, scientists have also seen negative epigenetic changes carried
through generations during times of famine. Populations exposed to famine
prenatally have suffered lower birth weights and higher-than-normal rates of
degenerative diseases, including diabetes, coronary heart disease and
But even when they received adequate nutrition in life, these populations
produced smaller-than-normal children and grandchildren. The initial adverse
environmental conditions affected at least two generations down the line
(Eur J Hum Genet, 2002; 10: 682-8).

Mice in Disneyland
But epigenetic changes aren’t simply caused by diet. Studies now show that
social and educational effects can also influence genetic expression.
Scientists studying genetics know how to manipulate genes so that certain
ones are turned on or off (or ‘knocked out’, as science indelicately puts
it). Recently, researcher Li-Huei Tsai, together with her team at the Howard
Hughes Medical Institute at the Massachusetts Institute of Tech-nology,
selectively bred a group of mice presenting with something akin to
Alzheimer’s disease, where the presence of a certain protein causes
degeneration of neurons in th
e brain.
These animals had profoundly impaired learning and memory, and impaired
long-term potentiation (LTP), a crucial cellular process for memory. In very
short order, after presenting with signs of brain atrophy and loss of
neurons, these mice become demented.
Up until now, scientists have believed that genetic coding is firmly fixed,
operating through a cascade of processes-involving proteins that affect
other proteins and then amino acids, like a game of dominoes-that ultimately
lead to the switching on (or not) of connections between neurons.
In her study, Professor Tsai subjected the altered mice to two tasks, both
designed to test memory and the ability to learn. The first was designed to
study whether these mice were capable of ‘fear conditioning’-where the
animals would have to undergo a task that ordinarily would cause them to
associate going into a specific chamber with receiving a mild electric
shock. In the second test, the mice had to find a sub-merged platform they’d
previously located in a tank, but after it was filled with murky water.
Ordinarily, such fear conditioning produces a long-term memory of the event;
once we burn our hands on the stove, we know forever after to steer clear of
a gas flame. Nevertheless, this group of mice failed both tasks; their
brains appeared to have deteriorated to the point where they could neither
learn from an unpleasant experience nor, indeed, retrieve information from
their memory storage about where an object was located.
However, having been impressed by studies showing that an ‘enriched
environment’ can improve learning capability, Tsai also wanted to test
whether this would apply in the case of animals that had already suffered
brain degeneration. So, in a second series of tests, she placed her
brain-damaged mice in an action-packed environment-along with other mice
they hadn’t met before, a treadmill, and a variety of brightly coloured,
variably shaped and textured toys-that was changed every day.
Later, when she and her fellow researchers again ran the animals through
both tasks, the mice that had been stimulated showed marked improvements
over those that hadn’t had the additional stimulation.
Also, when Tsai and her colleagues studied the brains of the stimulated
animals, they discovered that the environmental stimulation had altered
those parts of the cellular proteins and chemical tags that turn certain
genes on or off. In effect, the environment overrode the genetic blueprint
(Nature, 2009; 459: 55-60).
Genes were not destiny.

A good start

Dr Larry Feig and his research team, from the Sackler School of Bio-medical
Sciences at Tufts University, extended this idea to see whether a highly
educationally stimulating environment could override genes early on in life,
even in animals with major neural handicaps.
Feig and his team again used mice but, in this case, they knocked out the
Ras-GRF gene in a group of baby mice. Without this gene, a mouse lacks the
cellular processing critical for memory and learning, and has poor synaptic
efficiency in the brain, leading to poor information storage. And again,
mice without this gene cannot learn fear. When put in a potentially
unpleasant situation that they’ve already experienced and provided with the
stimulus that should set off a memory of the event, these mice don’t have
the foggiest memory of it.
In Feig’s study, the researchers exposed the 15-day-old mice to the
equivalent of a indoor theme park designed to stimulate new experi-ences.
This included a large cage
with play tubes, cardboard boxes, a running wheel, and toys and nesting
materials that were changed or rearranged every other day. After two weeks
in this enriched environment, the mice developed a compensatory brain switch
that turned on a new pathway to work with the Ras-GRF proteins to help with
their long-term memory and learning.
So, even though this gene had been ‘knocked out’ of these mice, a
stimulating environment effectively turned it back on. The mice showed every
evidence of normal memory and fear conditioning.
Feig then took this one stage further and examined what happened to their
offspring, which were given a normal environment rather than a
theme-park-enriched one. Astonishingly, the offspring of these mice also
showed evidence of normal memory and learning ability-even though they had
inherited the turned-off gene and they themselves had received no additional
stimulation (J Neurosci, 2009; 29: 1496-502).
The positive environmental effect of their ancestors again overrode their
genetic destiny. Indeed, in Feig’s study, the environmental effect turned on
the switch for several generations down the line.
This study also suggests the most radical idea of all-that a mother’s
positive diet and environment repre-sent a far more potent inheritance for
her children than ‘good genes’ on their own. An environment that is
constantly stimulating and socialized for mothers will have a bigger effect
on her children than their genetic heritage.
“If a similar phenomenon occurs in humans, the effectiveness of one’s memory
during adolescence, particularly in those with defective cell signaling
mechanisms that control memory, can be influenced by environmental
stimulation experienced by one’s mother during her youth,” the Tufts
researchers concluded (J Neurosci, 2009; 29: 1496-502).

The suicide gene

However, the opposite will also hold true: a negative environment can alter
genes to increase the likelihood of depression or mental illness. A recent
study has revealed the effect of the early environment on the likelihood of
suicidal depression. Moshe Szyf, a professor at the Department of
Pharmacology and Therapeutics at McGill Univer-sity in Montreal, examined
the brains of suicide victims and compared them with the ‘normal’ brains of
patients who had died of ordinary causes.
Although the genetic sequence was identical in both sets of brains,
fascinating differences appeared in the chemical coating-the ‘epi-genetic
markings’-of the brains of those who’d committed suicide. All 13 of the
suicides studied had suffered abuse as children, which may have caused the
changes in their epigenetic marks. However, at this time, it’s not yet
possible to definitively conclude whether or not the abuse directly led to
suicide (PLoS ONE, 2008; 3: e-2085).
A major study of schizophrenics by the Krembil Family Epigenetic Laboratory,
Centre for Addiction and Mental Health, in Toronto-and in association with
King’s College, London and University College London-used special laboratory
techniques to identify the chemical modifications (‘methylation’) in the DNA
of the frontal cortex in patients diagnosed with schizophrenia and biolar
They found changes in genes that were consistent with psychosis in the outer
casing of DNA, evidence of a strong link between schizophrenia and an
environmental cause. They even found such DNA changes in a patient who’d
been taking anti-psychotic medication for many years.
This and other data led the team to conclude that environmentally caused
changes in DNA may be an important factor in the development of
schizophrenia and bipolar disorder (Am J Hum Genet, 2008; 82: 696-711).
These new findings in epigenetics cast a long shadow on the idea that
illness is simply a crap shoot-a case of having ‘good’ or ‘bad’ genes.
Much of the work in epigenetics is new, and some findings are based on
animal studies and, therefore, may not apply to humans. However, taken
altogether, the implications of these data are profound. They reinforce the
idea that the on-off switches for genetic expression are controlled by
environmental triggers.
The new findings also suggest that the connection between a living t
hing and
its world, in the form of a good diet, clean water and air, good social
interaction, and a constantly stimulating and renewing environ-ment may be
the most potent healer of all-even of brain damage and genetic birth
Diet, a strong social network and community ties, purposeful work, mental
stimulation and an environ-ment free of extraneous pollution all go towards
deciding whether or not your body follows the genetic blueprint you were
born with. This suggests the most radical idea of all: our own health and
longevity are entirely within our control.
Lynne McTaggart

The other Darwin

More than half a century before Charles Darwin published his views on
natural selection in his book On the Origin of Species, the French botanist,
zoologist and philosopher Jean-Baptiste Lamarck had written, in 1802,
Recherche sur L’Organisation des Corps Vivants, the first book to set out a
coherent and well-developed theory of evolution, followed in 1809 by his
two-volume La Philosophie Zoologique.
Much as Darwin did after him, Lamarck believed in an evolving chain of
being. However, where Lamarck differed was in his belief that the
environment, rather than genetic coding, was responsible for changes in
animals and that these changes could also be inherited (now called ‘soft
Lamarck’s views were roundly rejected and he died a pauper, his family
destitute and his body buried in a lime-pit grave. However, his work was
revived in the early 1950s, when C.M. Waddington, a British lecturer at
Cambridge, carried out studies on fruit flies demonstrating that abnormal
conditions at early stages in their lives led to mutations that would also
be reproduced in eight generations of offspring.
Waddington exposed Drosophila to ether as embryos, after which the flies
developed a strange set of hind wings. Once a number of generations had been
exposed to ether, Waddington found that the altered hind-wing development
occurred in the offspring, even without exposure to the ether (Nature, 1952;
169: 278-9).
Waddington coined the term ‘epigenetic landscape’ to suggest that the
environment helps cells to differentiate into their various jobs. However,
mutation not only helped cell differentiation, but also caused changes that
were passed along to offspring.
Lamarck, who has been ridiculed up to now, particularly by the
neo-Darwinists, has indeed now been vindicated by many recent studies that
prove that environmental influences produce changes in an organism that
persist through subsequent generations.

The simple gene

The first chink in the idea of ‘genetic destiny’ was discovering, through
the Human Genome Project, that human genetic coding isn’t as complicated as
we first thought. As Francis Collins, director of the Human Genome Project
during 1993-2008, recently admitted, “First of all came the shock that we
didn’t have as many genes as we thought we did. People had been saying
100,000 [genes] for a long time. It’s probably only about 20,000 now that
the dust has really settled.”
Human beings, who are supposed to be the most complex organisms on the
planet, don’t have as many genes as most food, says Collins. By way of
comparison, a grain of rice has some 49,000 genes-nearly twice as many as a
human has.
These and other, more recent discoveries in biology and medicine render our
concept of the gene as the ‘Renaissance Man’ of the human body as out of
date. “A gene is just a packet of DNA,” says Collins. “We don’t even quite
know what the boundary is of that packet anymore.”
Currently, Collins is part of a team of researchers who are studying ‘junk’
DNA, the rough building blocks analogous to the junk in your basement. “Some
of it could be thrown out, but some of it you keep around in case some day
you need it.”

Mutants ‘r’ us

A new study by British scientists has finally determined that genetic
mutations are manifold and universal; indeed, all of us possess at least 100
mutations in our DNA.
The researchers, from the Wellcome Trust Sanger Institute in Cambridgeshire,
managed to isolate the mutations by studying thousands of genes in the Y
chromosomes of two Chinese men who were distantly related.
After studying their differences and comparing them with the entire human
genome, the team were able to extrapolate that every individual must have
around 100-200 mutations in their DNA.
Although these scientists believe that mutations lead to cancer and other
new diseases, and are the source of inherited variations, the new epigenetic
findings suggest that the environment may play an important role in whether
or not these mutations are expressed.

Vol 20 07 October 2009

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Article Topics: DNA, gene, genetics, protein
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