How Wolf Reik is unravelling life's other set of instructions at the Babraham Institute
Epigenome research impacts our understanding of ageing, disease and the development of embryos
In every human cell with a nucleus, you will find a copy of our genome: the complete set of DNA instructions for life, which comprises more than three billion base pairs.
So why aren’t all cells identical? If our cellular instruction manual is the same, how come we have liver cells, brain cells, blood cells and skin cells?
For the last three decades, scientists have been learning more about the significance of the epigenome – an additional set of instructions that alter how the genome behaves.
Professor Wolf Reik is associate director and head of the epigenetics research programme at the Babraham Institute.
He has just been awarded a £2.6million Wellcome Trust Investigator Award for research into how to reprogramme the epigenome.
The work could have far-reaching implications in this fascinating field, which impacts on our understanding of the development of embryos, the ageing process, and how diseases like cancer affect us, along with how we might combat them.
“When the genome was first discovered and sequenced there was huge excitement that genes could explain pretty well everything in our development and the diseases that we get,” Wolf explains to the Cambridge Independent.
“The genome is the blueprint for life. But what became apparent is that things were not quite as they seemed. For example, there’s the phenomenon of imprinting, where genes behave differently depending on whether they have been inherited from your mother or father. That doesn’t conform to normal genetics.
“I’ve been privileged to be around since the very early days, as a student and post-doc, and to grow up in the amazing field of epigenetics and see it come to life.”
The epigenome is a set of chemical compounds and proteins that influence how the genome behaves. These instructions are tagged to our DNA, to proteins that bind to DNA, or to chromatin – a complex of DNA, RNA and proteins. The chemical tags are known as epigenetic marks.
These marks alter gene expression – that is, they affect which of our genes are activated – and control the production of proteins in particular cells.
To use a modern analogy, your genome is a bit like your TV’s electronic programme guide, containing every channel available. But it takes a remote control – your epigenome – to select which one to switch on.
Our epigenome also changes through our life. Our diet, lifestyle and environmental factors can cause epigenetic change.
“If you think of our development, you start with one cell and then the cells divide and they are the same, but eventually they will form an organ – a liver, a kidney etc. They all become different.
“What is it that makes it different? The genome is the same. But the epigenetic make-up of a cell could potentially explain development, differentiation – how cells become different to one another – and then eventually how this plays out in disease and particularly during ageing.”
Wolf’s epigenetic research is exploring how our cells develop into these types in the developing embryo and, in the reverse of this process, how the memory of their identity can be erased so that cells can be reprogrammed back into unspecialised stem cells.
“The first thing that happens in the very early stages in germ cells – the pre-cursors to eggs and sperm – is an enormous wipeout of the epigenetic programme that occurs in adult cells. Most of the information is wiped out,” explains Wolf.
It’s as if someone had taken out the card to your TV’s set-top box – or cancelled your subscription...
“We call this global wipeout the reprogramming of epigenetic information. It brings the genome back to a stem cell state that enables it to start development afresh and to develop into new cell types.”
We have known about epigenetic reprogramming since the turn of the century, but in the last five years or so scientists have also been exploring how some of these instructions might escape the global wipeout, and be passed onto offspring – a process called epigenetic inheritance – over generations.
“It is particularly prominent in plants – not so prominent in mammals probably including humans,” says Wolf. “But it has been shown to occur in experimental animal models. When you feed mothers a high fat or low protein diet, some of the pups will have a different development. They will have, for example, metabolic diseases – diabetes-like symptoms.
“This is not a genetic phenomenon – it is purely an epigenetic phenomenon where something happened to the epigenome in the mother, which got inherited and caused the change in this physiology. The mechanism by which this happens is under intense investigation.
“It is likely to be epigenetic marks – chemical additions to the DNA from so-called methyl groups or changes to the chromatin environment, which happen in the egg and sperm.”
With the money from the Wellcome Trust Investigator Award, Wolf will recruit three new researchers to his Babraham lab and one of their aims will be to understand this global wipeout process at a molecular level.
“We want to identify factors, proteins and genes that drive this process with the ultimate aim that we could, in a mouse model, reverse the process and stop it from happening.
“This would allow us to test these big ideas about what the process is good for,” says Wolf.
“Does it make it difficult to achieve the stem cell state? Would it increase enormously the occurrence of epigenetic inheritance across generations in that model?
“Those are super exciting long-time aims. If we achieve them, it would be a huge step forward for the whole field.”
Companies in the Cambridge area are among those taking iPSC cells – induced pluripotent stem cells – from a person’s skin and converting them directly into stem cells, from which they can be made into brain cells, bloods cells or any others required for research or therapies.
“It is still the case that these cells are not perfect,” says Wolf. “They still have some kind of memory that they came from skin ultimately.
“Our research would contribute to understanding how we can wipe that memory completely clean and therefore make a proper stem cell that works really well in a therapeutic setting.”
Once past the global wipeout, the next stage for our cells is to be differentiated into all the cell types our body needs.
Epigenetic marks are key here and affect whether ‘transcription factors’ – proteins that bind to DNA – are able to drive gene expression.
DNA methylation, for example, adds methyl groups to a DNA molecule, without changing its sequence, and in doing so turns a gene off. It’s a bit like a mute button on our epigenetic remote control.
“If you think of a brain specific transcription factor which would normally drive the gene expression programme in the brain, then if it’s prevented by DNA methylation from doing its work, then the cell can’t become a brain cell and could become a liver cell, for example.
“So the epigenetic marks that sit on the DNA help the DNA to switch from one programme to another – and to remember that programme.
“When a liver cell divides, it remains a liver cell. Only in a cancerous process could it lose that identity and change,” says Wolf.
“In cancer, something quite similar happens to the global wipeout that occurs in early development.
“There are a number of things that go wrong in the cancer that are epigenetically driven, in addition to the mutations that the cancer has in the DNA. And there is an interplay between these processes.”
Researchers are beginning to explore how this might help us fight cancer.
“One of the things that can go wrong are tumour-suppressing genes – which defend against cancer – becoming epigenetically inactivated,” says Wolf. “There are drugs that can reverse this epigenetic inactivation. That’s exciting – it’s not like a DNA change that is much harder to reverse. The interesting thing about epigenetic change is that in principle you can reverse it, which offers us much broader ideas about therapy.
“There are drugs in clinical testing for myelodysplastic syndrome – a horrible blood cancer – and in many patients they have shown very positive effects.”
The Investigator Award will help fund the study of the process by which cells become differentiated and so improve stem cell therapies.
“If we understand the molecular epigenetic steps of how that occurs in the body, we can better manipulate that process,” says Wolf.
“Assuming we have really good stem cells in hand, the next step is to convert them into cells that work and function in the body. That’s quite a long step in a culture dish.
“If we understand better the switches that occur as you go from a stem cell to a liver cell, we can enhance that process for the therapeutic application of stem cells.
“You start with skin cells, convert them back into stem cells, and then – partly in a dish and partly in the body eventually – convert them into normally functioning liver cells in the patient.”
Our understanding of epigenetics has come a long way in 30 years.
It could progress rapidly in the next five.
Could we turn back the ageing clock?
Wolf Reik’s team put on an exhibition at the Royal Society in London called ‘Race against the ageing clock’ earlier in the summer, which explored the role of epigenetics in ageing and the potential of regenerative medicine to reprogramme or reset this clock.
“There are two main ideas in the ageing field,” explains Wolf, who was elected to the Royal Society in 2010. “One is that it’s an accumulation of wear and tear, of mistakes and mutations to the genome as we get older – more or less a random process of damage that accumulates.
“The other way of thinking about ageing is that it’s a programme that ticks away as we age. We are quite excited about this second idea.
“What we and others have found is that there is an epigenetic clock, or ageing clock, ticking in our bodies, which in the first instance measures our chronological age. If we took blood from you, we could predict your age by plus or minus 3.6 years, which is pretty accurate.”
Analysis of DNA methylation can also provide information on our biological age.
“If we were 100 years old, our epigenetic clock or DNA methylation clock would read, let’s say, 91 years, which means that as we age it ticks more slowly. Or if we have a fatty liver disease, in that organ, the epigenetic ageing clock ticks faster.
“So it’s a chronological clock but it’s modified – ticking faster or more slowly – by biological and dietary influences, by exercise and smoking etc. It’s a fascinating idea and in principle this clock can be changed and reversed.”
Taking skin cells back to stem cells is effectively a process of resetting the clock.
“It offers, in theory, the prospect of winding back this clock in a more controlled way, by understanding its mechanism better and then fiddling with the molecular components to change the ticking rate.
“For example, if degenerative diseases in the brain, such as Alzheimer’s, turned out to have a component related to this ageing clock, you could think about doing this with brain cells and transplanting them back.”
A baby girl born in 1841 could expect to live just beyond her 42nd birthday – one born in 2016 can expect to live until the age of 83.
In June, the Cambridge Independent spoke to controversial gerontologist Aubrey de Grey, who suggested it was possible to extend human healthspan – how long we live healthy lives – dramatically, so we could live to 1,000 years or more.
“I’m more sceptical about it,” says Wolf, who completed his training as a medic in 1985, before entering the nascent field of epigenetics. “Improvements of healthspan are possible to think about in relation to the ageing clock. But the ageing clock is not the only thing that causes ageing. Probably wear and tear also occurs and that’s far more difficult to reverse, I think. But extending healthspan is a very important aim.”
The research has already given birth to a company, called Chronomics, which uses epigenetic measurements from saliva samples to give feedback to customers on their health, as the Cambridge Independent has reported. The company was co-founded by Tom Stubbs, who was a PhD student in Wolf’s lab and helped develop the concept of the ageing clock.
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