Horizon - Epigenetics - The Ghost In Your Genes

Biology stands on the brink of a shift in the understanding of inheritance. The discovery of epigenetics -- hidden influences upon the genes -- could affect every aspect of our lives.

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At the heart of this new field is a simple but contentious idea -- that genes have a 'memory'. That the lives of your grandparents -- the air they breathed, the food they ate, even the things they saw -- can directly affect you, decades later, despite your never experiencing these things yourself. And that what you do in your lifetime could in turn affect your grandchildren.

The conventional view is that DNA carries all our heritable information and that nothing an individual does in their lifetime will be biologically passed to their children. To many scientists, epigenetics amounts to a heresy, calling into question the accepted view of the DNA sequence -- a cornerstone on which modern biology sits.

Epigenetics adds a whole new layer to genes beyond the DNA. It proposes a control system of 'switches' that turn genes on or off -- and suggests that things people experience, like nutrition and stress, can control these switches and cause heritable effects in humans.

In a remote town in northern Sweden there is evidence for this radical idea. Lying in Överkalix's parish registries of births and deaths and its detailed harvest records is a secret that confounds traditional scientific thinking. Marcus Pembrey, a Professor of Clinical Genetics at the Institute of Child Health in London, in collaboration with Swedish researcher Lars Olov Bygren, has found evidence in these records of an environmental effect being passed down the generations. They have shown that a famine at critical times in the lives of the grandparents can affect the life expectancy of the grandchildren. This is the first evidence that an environmental effect can be inherited in humans.

In other independent groups around the world, the first hints that there is more to inheritance than just the genes are coming to light. The mechanism by which this extraordinary discovery can be explained is starting to be revealed.

Professor Wolf Reik, at the Babraham Institute in Cambridge, has spent years studying this hidden ghost world. He has found that merely manipulating mice embryos is enough to set off 'switches' that turn genes on or off.

For mothers like Stephanie Mullins, who had her first child by in vitro fertilisation, this has profound implications. It means it is possible that the IVF procedure caused her son Ciaran to be born with Beckwith-Wiedemann Syndrome -- a rare disorder linked to abnormal gene expression. It has been shown that babies conceived by IVF have a three- to four-fold increased chance of developing this condition.

And Reik's work has gone further, showing that these switches themselves can be inherited. This means that a 'memory' of an event could be passed through generations. A simple environmental effect could switch genes on or off -- and this change could be inherited.

His research has demonstrated that genes and the environment are not mutually exclusive but are inextricably intertwined, one affecting the other.

The idea that inheritance is not just about which genes you inherit but whether these are switched on or off is a whole new frontier in biology. It raises questions with huge implications, and means the search will be on to find what sort of environmental effects can affect these switches.

After the tragic events of September 11th 2001, Rachel Yehuda, a psychologist at the Mount Sinai School of Medicine in New York, studied the effects of stress on a group of women who were inside or near the World Trade Center and were pregnant at the time. Produced in conjunction with Jonathan Seckl, an Edinburgh doctor, her results suggest that stress effects can pass down generations. Meanwhile research at Washington State University points to toxic effects -- like exposure to fungicides or pesticides -- causing biological changes in rats that persist for at least four generations.

This work is at the forefront of a paradigm shift in scientific thinking. It will change the way the causes of disease are viewed, as well as the importance of lifestyles and family relationships. What people do no longer just affects themselves, but can determine the health of their children and grandchildren in decades to come. "We are," as Marcus Pembrey says, "all guardians of our genome."

We are on the brink of uncovering a hidden world.

A world that connects past and future generations in ways we never imagined possible.

What this means is

an environmental exposure that your grandmother had could cause a disease in you -

even though you've never been exposed to the toxin -

and you are going to pass it on to your great-grandkids.

These extraordinary discoveries have the potential to affect every aspect of our lives.

It's not just the genes, but also the environment in the early life of your ancestors.

It's not so much "you are what you eat,"

it's that you are what your mother ate, and maybe you are what your grandmother ate.

And if you take our data, you are what stress your grandmother or grandfather had.

It will change the way we think about our relationship with every generation.

It makes me feel closer to my children.

What I experience, in terms of environment,

will have some type of a legacy in my children and my grandchildren.

The science of inheritance is being turned on its head.

We're changing the view of what inheritance is.

This small Swedish town may hold the evidence to launch a medical revolution.

Overkalix lies huddled on the edge of the Arctic Circle.

Inaccessible and remote, it was cut off from the rest of the world for most of its history.

Marcus Pembrey has traveled here to meet his colleague Olov Bygren.

They believe that the story lying buried in these graveyards

may hold the proof to their radical ideas.

This group of people could contribute to ...

really a sea change in the way we think about inheritance.

They have come to this churchyard to find grandmothers and granddaughters, grandfathers and grandsons.

Connecting people who lived almost a hundred years apart in entirely new ways.

Uncovering links that confound scientific thinking.

Up 'til now, inheritance is just the genes; the DNA sequence.

I suspect that we are going to be able to demonstrate that the inheritance is more than that.

It is the culmination of more than twenty years' work.

And for the first time, Pembrey is confronting the magnitude of their discovery.

It really has come alive for me - coming here - more than I had expected.

It re... I'm really quite sort of emotional about it. Wonderful!

Marcus Pembrey is one of a select band of scientists.

A band of scientists who are daring to challenge an orthodoxy.

They believe the lives of our parents, grandparents, and even our great-grandparents can directly affect our well-being,

despite never experiencing any of these things ourselves.

To many, these ideas are regarded as scientific heresy.

You cannot predict where discoveries will be.

The only thing you can do is to follow your instinct.

Conventional biology has always believed that our genetic inheritance is set in stone at the moment of our conception.

At that instant we each receive a set of chromosomes from both our mother and father.

Within these chromosomes are the genes: strips of coded DNA, the basic unit of inheritance.

After conception it was assumed that our genes are locked away inside every cell of the body,

protected and untouched by the way you live.

So, what you do in your life may affect you, but your genes remain untainted, unchanged for future generations.

In classic genetics, your parents and grandparents simply pass on their genes.

The experiences they accumulate in a lifetime are never inherited -

- lost forever as the genes pass untouched through generation after generation.

The biology of inheritance was a reassuringly pure process,

or so it seemed.

In the early 80's, Marcus Pembrey headed the clinical genetics department at Great Ormond Street Hospital for Children.

He was frequently treating families with unusual genetic conditions.

We were constantly coming across families which didn't fit the rules,

didn't fit any of the patterns that genetics were supposed to fit.

So you think of chromosome abnormalities and you check the chromosomes and they're normal,

so you then have to start imagining - as it were - you know, what might be underlying this.

And you were really driven to try and work it out because the families needed some help.

The more families he saw, the more the rules of inheritance appeared to break down.

Diseases and conditions that simply didn't fit with the textbook conventions.

One condition in particular caught his eye: Angelman's syndrome.

Named after Harry Angelman, the pediatrician who first described Angelman's syndrome.

He referred to them as "Happy Puppet" children, because it described to some extent the features.

They have a rather jerky sort of movement when they're walking.

These children have no speech, they are severely incapacitated in terms of learning,

but are uncharacteristically happy, and they're smiling all the time.

The condition was caused by a genetic fault: a key sequence of DNA was missing, deleted from chromosome fifteen.

Then we came across a paradox.

At the same time, the same change - the same little deletion from chromosome fifteen -

- had been clearly associated with a quite different syndrome much milder in terms of intellectual impairment: the Prader-Willi syndrome.

These children are characterized by being very floppy at birth,

but once they started eating properly and so on, they then had an insatiable appetite and would get very, very large.

What Pembrey saw simply made no sense.

Here were two completely different diseases -

- Angelman's syndrome and Prader-Willi syndrome - being caused by exactly the same genetic fault.

So here we had a very bizarre situation, really.

How could anyone propose that the same deletion could cause a different syndrome?

It appeared to Pembrey as if the simple view of inheritance was beginning to unravel.

But his doubts were contrary to the tide of optimism sweeping the scientific community.

In the early 1990's, the biggest project ever undertaken in biology was captivating the world.

The Human Genome Project will be seen as the outstanding achievement in the history of mankind.

The Human Genome Project was to be the pinnacle of a century of work on genes and genetics.

It seemed as if the secrets of life were at our fingertips.

The genetic blueprint of mankind.

Mapping out maybe the whole human genetic code.

It's a set of instructions to make a human being.

The human genome is like a bible where everything was written down.

The hope and the expectation was that once we had that book in front of us - and all the letters -

- we could just read down the pages and we would understand how the body was put together.

It would offer a complete understanding of human biology at the molecular level.

The hope was that once the code was written down, scientists could find the genetic cause and cure for every disease.

... could lead to the end of diseases like cancer, Parkinson's, Alzheimer's, diabetes ... the list is endless.

We were thinking of genes in a very mechanical way.

We were thinking of them just in terms of the sequence of the letters.

We were all working out how we could work out what all the letters were in the book.

Scientists estimated that the human genome - the book of life - would contain around a hundred thousand genes.

And then when they started sequencing, they realized that maybe a hundred thousand genes,

then it popped down to sixty, and then it popped down to fifty,

and slowly it went down to a much smaller number.

In fact, we found out that the human genome is probably not as complex

and doesn't have as many genes as plants do.

So that then made us really question, "Well, if the genome has less genes in this species versus this species, and we're more complex potentially,

what's going on here?"

Now scientists estimate there are probably less than thirty thousand genes.

We believed - I believed naively - that we would be able to find the genetic components of common diseases.

And that's proven to be very difficult.

The idea of "one gene, one disease" does not explain it all.

Thirty thousand genes didn't appear enough to explain human complexity.

There had to be something they'd missed.

The first hints of what was missing lay in the curious paradox of the Prader-Willi and Angelman's syndromes -

- two quite different diseases caused by exactly the same genetic fault.

When Pembrey looked at the inheritance pattern for the conditions, he noticed something even stranger.

What really mattered was the origin of the chromosome fifteen that had the deletion.

If the deletion was on the chromosome fifteen that the child had inherited from father,

then you'd have Prader-Willi syndrome,

whereas if the deletion was inherited from the mother, you had the Angelman's syndrome.

It was a complete surprise that the same missing strip of DNA could cause one disease when it came from the mother,

and a completely different disease when it came from the father.

It was as if the genes knew where they came from.

You've got a developing fetus manifesting this condition ... how does the chromosome fifteen know where it came from?

It - there must have been a tag or an imprint placed on that chromosome

during either egg or sperm formation from the previous generation

to say, "Hi! I came from mother. I came from father.

And we are functioning differently."

So that's the key thing: that although the DNA sequence is the same,

the different sets of genes were being silenced depending on whether it came from the mother or from the father.

It showed that there was clearly more to inheritance than simply the coded sequence of DNA.

We then realized that we were dealing with what is now known as genomic imprinting.

What genomic imprinting means is, in a nutshell, that genes have a memory of where they came from.

Something other than just the DNA was capable of moving between generations.

It was a tantalizing glimpse into this unknown and unexpected world.

A hidden layer acting on, and able to directly control, how our genes function.

It meant that inheritance was not simply about which genes you inherited,

but whether those genes were silenced; switched on, or off.

And you can think of it as a light switch.

Switch on the gene, the light is shining, the gene is active, it makes the cell do a certain thing;

or the light switch is off, everything is dark, that gene is off.

The switches remain on or remain off. And that gives the cells their identity.

The activity of genes was being controlled by a switch:

the attachment of a simple chemical which dictated whether the gene was switched on or off.

Whether those genes are turned on or off is called epigenetics.

Epigenetics. You know, "upon" the genes.

Not only is the sequence important of the DNA, which we've studied for a long time, (the past few decades)

but we now understand that in addition to that

there's this overlying epigenetic phenomenon that allows the genes to get turned on or off.

Epigenetics could explain how a human could be created with less than thirty thousand genes,

and why the genome project didn't provide all the answers.

Now if we actually put epigenetics on top of it -

- where it makes it much more complicated on whether genes get activated to a certain level and so forth -

- then you have a complexity that can start to explain biology much more effectively than the simple sequence of the DNA.

So clearly we have additional levels of complexity that we now need to understand that are well beyond the DNA.

The next huge challenge for modern biology is to now decipher the epigenetic code

and to understand all the combinations of switches that exist.

An accurate chemical map of the human genome tells us surprisingly little about how it actually works.

Transcribing the code of the genes - the genome project - is not an end, but simply a beginning.

If inheritance was not just about DNA, if these gene switches were so important, just what could turn them on, or off?

Stephanie and Amon Mullins have two children: Ciaran and Charlotte.

When you are trying to conceive, and you see all your friends around you getting pregnant, having children,

as each month went on you become more and more desperate.

Doctors recommended IVF treatment.

In the UK alone, around eight thousand babies are conceived every year using assisted reproduction techniques like IVF.

After the third attempt, Stephanie became pregnant with Ciaran.

At the time they didn't really highlight any risks to us.

And then we went for a routine scan, and I did feel that the scan was taking an awful long time.

Basically what they'd found was something called an exomphalus on Ciaran's abdomen,

which basically means that part of the bowel is still on the outside of the abdomen.

Doctors suspected that Ciaran might be suffering from Beckwith-Wiedemann syndrome,

a rare condition where babies are born very large, often have oversized tongues, and have a high risk of developing childhood cancers.

They couldn't say one hundred percent that the baby did have Beckwith-Wiedemann syndrome,

but it was showing signs.

They could see his tongue protruding on the scan,

and he said that he had very big thighs,

but until Ciaran was actually born, we didn't know how severely affected he was going to be.

When Ciaran was born, it was clear he did indeed have Beckwith-Wiedemann syndrome.

Within a few hours of the birth,

Ciaran had to have surgery to have the bowel that was on the outside of the abdomen basically put back inside, repaired.

Ciaran also had surgery to reduce the size of his tongue, and every few months he has scans to check for tumors.

Cases of Beckwith-Wiedemann syndrome caught the attention of Wolf Reik.

Wolf Reik worked in developmental genetics.

He was fascinated by the emerging epigenetic ghost world.

He wanted to know what could throw the switches on or off.

To his surprise, he found that simply placing a mouse embryo in a culture dish could trigger genes to switch off.

After we had seen how relatively easy it was to change the switches in mouse embryos,

we thought that perhaps the same could be true of human embryos.

In IVF you also have the embryo for a brief period of time in a culture dish.

And so we were asking the question whether, as in the mouse embryo,

the mere fact of human embryos having been in a culture dish or being manipulated could alter their epigenetic switches.

Wolf knew that Beckwith-Wiedemann syndrome was caused by a faulty switch.

So what we were looking at was a group of babies and children that have Beckwith-Wiedemann syndrome.

What proportion of those were conceived by IVF?

Could IVF be switching genes on or off? Could IVF itself cause the syndrome?

What we found was an increased occurrence of this epigenetic syndrome in the IVF population.

Although the disease is extremely rare, the risk appeared to increase three to four times with IVF.

It seemed that the simple act of removing the embryo from its natural environment could trigger the disease.

And we do feel frustrated that Ciaran might possibly have Wiedemann syndrome because we had IVF.

But at the time it was the right decision to make.

And I think that's why we should look again at the IVF procedures,

the conditions that are being used,

and carry out better and more precise experiments to see how we can avoid throwing these epigenetic switches.

Wolf had shown a simple change in environment was enough to turn a gene on or off, but there was more.

Everyone thought that any altered switches could not be inherited.

He took some mice with altered gene switches and bred them.

Our expectation was that as the altered genome was passed to the children that any epigenetic changes would be wiped clean.

When he looked at the gene profile of the offspring he was amazed.

You have dots that we were looking at, and every dot means a gene is on.

And all of the sudden you know somebody said, "Wow - look at that."

The epigenetic switch thrown in one generation was clearly also present in the second generation.

Nobody had seen this kind of thing before. This was the first time.

And all the people looking at the gel and saying, "No, this can't be right, it's the wrong gel."

And you know, you get excited about it and you think, "Oh, maybe this is wrong," and you're not on the right track.

And we were very excited - as excited as scientists ever get.

This meant that the genes were not locked away.

A simple environmental event could affect the way genes worked.

And that could be inherited, as if a memory of an event was being passed down through generations.

It was something many scientists regarded as impossible.

If this effect could be observed in humans the implications would be profound.

It would mean that what we experience could affect not just us, but our children and our grandchildren.

While these observations were just emerging from laboratories, Pembrey was still working at Great Ormond Street.

He began to wonder why these links between generations would exist.

Now my reputation was made as a clinical geneticist, so I was much freer to speculate outside my main career.

I also like to stir things up a bit. And it amuses me to speculate because I've got nothing to lose.

And if I'm right, well then that's very amusing.

He speculated why genes would carry a memory from one generation to the next.

What evolutionary purpose could it serve?

Maybe imprinting was used as a means of some sort of trans-generational adaptation.

He thought it could be used for a mother to send messages to her baby in the next generation.

Something that always puzzled me ever since I was a medical student was

what stops the baby's head jamming up in the birth canal?

The baby was grown in one generation, but the mother's pelvis was grown in the previous generation.

So if the mother was starving when she was growing, (so she had a small pelvis)

maybe her eggs had captured that information and so they were instructing the growth genes of the future babies to not work so much,

and for the baby not to grow too much so as to jam up the birth canal.

So, there was some sort of coordination between growth in two generations.

That struck me as entirely reasonable.

He published his ideas in an obscure journal and largely forgot about it.

After all, there was no evidence for any of this. It was pure speculation.

Then four years later Marcus received an email from a doctor in Sweden.

It really came as a bolt out of the blue.

I'd just got an email in May 2000 saying my paper was the only thing he could find in the literature that in any way sort of tied in with his basic observations.

The email was sent by Olov Bygren.

He was studying the population records of an obscure town in northern Sweden: Overkalix.

What made these records unique was their detail.

They recorded births and deaths over hundreds of years.

They also had accurate details of the harvests.

More significantly, Overkalix's isolated location on the Arctic Circle meant that it was particularly vulnerable to famine.

In the nineteenth century this was a very isolated area.

They could not have help from outside.

As it was so poor, they really had a hard time when there was a famine.

And they really had a good time when the harvests were good.

Bygren appeared to be seeing links between generations that confounded his expectations.

I sent Marcus Pembrey an email telling him that we had some data which could interest him.

I was terribly exited to get this completely out of the blue,

and for the first time it seemed that there was some data that we could then start to explore.

So that was the beginning of our collaboration.

Overkalix offered Pembrey a unique opportunity

to see if the events that happened in one generation could affect another, decades later.

While Pembrey and Bygren sifted through the Overkalix data,

someone else had stumbled on another group of people that caught them by surprise.

Rachel Yehuda is a psychologist. She's interested in how people respond to stress.

Well trans-generational effects were not on my radar screen at all, until we opened up a clinic for the treatment of Holocaust survivors.

While treating the Holocaust survivors for stress,

she was surprised that many of the children of the survivors were themselves suffering stress effects.

About five children of Holocaust survivors were calling us for Holocaust survivor,

and what these children said is that they were casualties of the Holocaust too - that they had been affected by the Holocaust indirectly.

She was convinced that the stress in the children was caused by continual re-telling of the stories by their parents.

Our studies had really convinced me

that it were the early experiences of the child as the child was growing up bombarded with years and years of symptoms from the parents

that accounted for the effect that we observed.

However, in Edinburgh, Jonathan Seckl was interested in stress exposure in pregnant women

and wondered if stress effects could be transmitted to their children.

He started some experiments with pregnant rats to see if exposing them to stress hormones had any effect on their offspring.

And we found the next generation, for the rest of their lifespan,

those animals had altered stress responses and showed behavior that looked like anxiety.

To see if this was affecting the genes themselves,

he decided to breed them and see if the stress effects could be found in generations never exposed to the stress hormone.

And their daughters and sons also got the propensity for abnormal stress responses.

For Seckl the only explanation was that a stressful event was throwing a switch on a gene which was then being inherited.

His work might have stopped there, until world events took a hand.

When on 9-11 the planes crashed and the towers came down,

Yehuda and Seckl were critically aware of the potential for the impact to be far-reaching - even affecting generations yet to be born.

Ailsa Gilliam was working in a building next to the towers.

As I left my building coming out through the doors, there was a lot of ash floating through the air, and some office papers.

I knew that if I looked up I may see something I didn't want to see.

Just the thought that people had died close to me? I broke down. I got very upset.

Well I wanted to get out of the environment.

Being pregnant, I did not want to open myself up to more emotional uncertainty and emotional distress.

After the events of 9-11 unfolded, Yehuda and Seckl teamed up to study women like Ailsa who were pregnant at the time.

There were a lot of different opportunities to examine what the effects of 9-11 would be

on the children who might be born to parents who developed Post-Traumatic Stress Disorder in response to 9-11,

and particularly those who had been exposed in utero.

When exposed to a stressful event a person produces cortisol, a hormone that helps regulate the body's response to that stress.

If cortisol levels are too low, a person finds coping with stress very difficult and are prone to PTSD: Post-Traumatic Stress Disorder.

But could this effect be transmitted to their offspring?

They found nearly two hundred women of whom a number had actually been in the twin towers.

About half of them developed Post-Traumatic Stress Disorder.

We then looked at those women and found they had abnormal cortisol in their saliva.

The most striking finding was, so did their babies.

The argument in the Holocaust survivors had been that

their children showed abnormal stress hormones

because they themselves had been stressed by listening to the tales recounted by their parents of their awful exposures during the 1940's.

That could not be the case with the 9-11 survivors. These babies were one year old.

Not only did infants have lower cortisol levels, but they were different depending on how pregnant the mother was on 9-11.

The main effect was only seen with those mothers with PTSD who were pregnant in the last third of pregnancy.

Mothers with equal levels of PTSD who were pregnant in the first and second third of pregnancy at 9-11 ...

... it was very little effect on the baby's cortisol.

It suggested to us that it couldn't just be about genetics,

but there was something that was being transmitted in the late stages of pregnancy

where the mother's symptoms were having some effect on the development of the offspring's cortisol system.

It appeared that epigenetics might be responsible; that an event had altered the stress response in the children.

What these findings did was suggest to us

that we need to be looking where we hadn't even considered looking before.

To know for certain that this was an epigenetic effect

they'll need to be sure that their observations weren't simply due to high levels of stress hormones in the womb.

Now, (and here is the bit where we have to speculate)

the animal work would suggest that this might then persist into the next generation.

If they find the same stress effects in the children's children of 9-11

then it will be clear that a genetic memory of a stressful event can travel through the generations.

That's the key thing next to find out.

But the 9-11 population will be very, very important for us to be able to follow what is a single discrete event.

The work of Yehuda and Seckl offers tantalizing evidence of proof of inherited epigenetic effects in humans,

but they need data that extends beyond just one generation.

The only way forward was to look back to the past.

In Sweden, Pembrey and Bygren had data that provided the chance to study the effects of famine through many generations.

Olov Bygren was looking to see if poor nutrition had an effect on health, when he stumbled on something curious.

It appeared that a famine could affect people almost a hundred years later, even if they never suffered a famine themselves.

He wanted to know how this might be possible, so he asked Marcus Pembrey.

Olov first reported that the food supply of the ancestors was affecting the longevity or mortality rate of the grandchildren.

So I was very excited. I responded immediately.

Pembrey had a hunch that the incidents of one disease, diabetes, might be an indicator that epigenetics was involved.

Specifically I wanted to know the results of the diabetes because this was the one that I thought might involve the imprinting.

So Olov trawled the records for any deaths due to diabetes

and then looked back to see if there was anything unusual about the diet of their grandparents.

A few months later, he emailed me to say that indeed they had shown a strong association

between the food supply of the father's father and the chance of diabetes being mentioned on the death certificate of the grandchild.

So of course I was really rather excited by that

because it really did look as if there was some trans-generational effect going on there.

It looked as if there were clear links through the generations between grandparents and grandchildren.

They found that the life expectancy of grandchildren was being directly affected by the diet of the grandparent.

It appeared that Overkalix held the key to finding the first evidence of epigenetic inheritance in humans.

It really did look as if there was some new mechanism transmitting environmental exposure information from one generation to the next.

Because these ideas were so heretical, Pembrey knew these results could be dismissed as nothing more than a curiosity.

They needed to get an understanding of how all this was happening.

How could the grandparent capture the information that was affecting the grandchildren?

We wanted to tease out when you could trigger in the ancestor a trans-generational response.

So he and Bygren went back to the data and looked again.

The more they looked, the more patterns started to appear.

We were able to look at the food supply.

Every year in the grandfather and the grandmother from the moment they were conceived right through until the age of twenty.

We found that there were only certain periods in the ancestor's development

when they can trigger this trans-generational response - their, what one might call, "sensitive periods" of development.

They discovered that when a famine was able to trigger an effect was different for the grandmother than the grandfather.

The grandmother appear susceptible while she herself was still in the womb,

while the grandfather was affected just before puberty.

And the timing of these sensitive periods was telling us

that it was tied in with the formation of the eggs and the sperm.

This was critical, because now they knew how it was happening.

Environmental information was being imprinted on the egg and sperm at the time of their formation.

At last a clear picture of an inherited environmental effect was beginning to emerge.

All they needed to do now was to compile their findings.

Bygren drew up a rough diagram and sent it to Pembrey.

Hand-drawn, this is what Olov sent me.

You know, he was too excited to wait for the thing to be drawn out, probably.

You know, he sent me the data.

And in fact I was recovering from having something done to my heart,

so he sent it saying, "I hope this helps you get better quickly," because he was so excited.

When Pembrey plotted out the diagram, he was immediately struck by its significance.

Once I had plotted out the full extent of those results, it was so beautiful and such a clear pattern.

I knew then quite definitely that we were dealing with a trans-generational response.

It was so coherent.

And that's important in science, that the effect was coherent in some way.

It was tying in when eggs and sperm were being formed.

The diagram showed a significant link between generations: between the diet in one and the life expectancy of another.

When you think that you have found something important for the understanding of the science itself you can then imagine that this is something really special.

It's up there with - I'm a sort of fair weather supporter of Liverpool -

- it's up there with Liverpool winning the Champions League.

You can only have it once in your lifetime.

This is going to become a famous diagram, I'm convinced about that.

I get so excited every time I see it.

It's just amazing. Every time I look at it I find it really exciting. It's fantastic.

Pembrey and Bygren have the first conclusive proof of an environmental effect being inherited by humans.

The impact of a famine being captured by the genes in the eggs and sperm,

and a memory of this event was being carried forward to effect the grandchildren generations later.

We're changing the view of what inheritance is.

You can't in life - in ordinary development and living - separate out the gene from the environmental effect, they're so intertwined.

Pembrey and Bygren's work showed clearly that what our grandparents ate could affect our health.

Increasingly, it appeared as if all sorts of environmental events were capable of affecting the genes.

And in Washington State, Mike Skinner stumbled on some results with profound implications.

He triggered an effect with commonly used pesticides and fungicides.

He exposed a pregnant rat to a high dose of one of these pesticides and then looked for effects in her offspring.

And so I treated the animals (the pregnant mother) with these compounds,

and then we started seeing - between six months to a year - a whole host of other diseases that we didn't expect.

And this ranged between tumors such as breast and skin tumors, prostate disease, kidney disease, and immune dysfunction.

He bred these rats to see if the effects persisted into subsequent generations.

The next step was for us to go to the next generation, and then go to the third generation out, and the same disease state occurs.

So after we did several repeats and got the third generation showing it and then a fourth generation

we sat back and realized that the phenomenon was real.

We started seeing these major diseases occur in approximately eighty-five percent of all the animals of every single generation.

His discoveries were a revelation.

We knew that if an individual was exposed to an environmental toxin that they can get a disease state potentially.

The new phenomenon is that an environmental toxin no longer affects just the individual exposed,

but two or three generations down the line.

I knew that epigenetics existed,

I knew that it was a controlling factor for DNA activity where the genes are silenced or not,

but to say that epigenetics would have a major role in disease development ... I had no concept of that.

The fact that this could have such a huge impact

and could explain a whole host of things we couldn't explain before took a while to actually sink in.

The exposure of a single animal to a toxin was causing a whole range of diseases in almost every individual of the following generations.

And because epigenetic effects have been observed in humans this may have implications for us, too.

What this means then is what your grandmother was exposed to when she was pregnant

could cause a disease in you

even though you had no exposure

- and you're going to pass it on to your great-grandchildren.

The work of these scientists is at last throwing a spotlight onto the mysterious hidden world of epigenetics.

They appear to show that the lives of our ancestors have a capacity to affect us directly.

These results are provocative. Some find them difficult to accept.

But it's quite clear now that a number of laboratories are finding similar findings in the various systems that they are interested in.

So the phenomena are there.

Epigenetics has the capacity to reach into every aspect of our lives,

and links our past, present and future in previously unimagined ways.

I think this will be the next revolution in molecular biology.

This really could be a paradigm shift we really did not expect. It could explain a lot of things.

There are many diseases - very common diseases such as Alzheimer's disease of the brain, diabetes -

- which are very difficult to explain currently genetically.

Maybe a lot of these kind of very common diseases are actually caused by epigenetic switches.

We are just at the beginning. There is much that is unknown.

But what is clear is that it will change the way we think about ourselves forever.

I've thought of nothing else, really, for the past five years.

It is said the first time one had a photograph of the earth -

- you know, this sort of delicate thing sailing through the universe -

- it had a huge effect on the sort of "save the planet" type of feeling.

I'm sure that's part of why the future generation thinks in a planetary way, because they've actually seen that picture, you know.

And this might be the same.

It may get to a point where they realize that you live your life as a sort of guardian of your genome.

You've got to be careful of it because it's just not you.

You can't be selfish because you can't say,

"Well I'll smoke, or I'll do whatever it is, because I'm prepared to die early."

You're also looking after it for your children and grandchildren.