Epigenetics

//Entrevista a Manel Esteller, director del Programa de Epigenética y Biología del Cáncer del Instituto de Investigación Biomédica de Bellvitge y profesor de la Universidad de Barcelona

“If our DNA is like an alphabet, with its own rules for building words and making sense, then the epigenome is the record that regulates the alphabet.” This simple but graphic explanation of epigenetics comes from one of science’s main authorities on the subject: Manel Esteller. Doctor in Medicine from the University of Barcelona, where he lectures,  Esteller completed his training at the School of Biological and Medical Sciences of the University of St. Andrews (Scotland, UK), and at Johns Hopkins University School of Medicine (Baltimore, MD, USA). Former director of the Epigenetic Cancer Laboratory at the National Centre for Oncology Research in Madrid, he currently leads the Epigenetics and Cancer Biology Programme of the Bellvitge Institute for Biomedical Research, in Barcelona, and also teaches at the Catalan Institute for Research and Advanced Studies. A prominent author, Esteller has received numerous prizes for his work on epigenetics, and has also just published the book Aposta per la salut! (‘Value your Health!’) (Edicions 62). 

So what exactly is epigenetics?

Epigenetics is the study of the chemical marks that attach themselves to our genetic material so that it works properly. The example we most typically use to explain epigenetics is of identical twins, which are created when one fertilized egg splits and develops into two babies. The babies have exactly the same DNA but can grow up to become different individuals who even get different illnesses. This is because although they have the same compliment of genes, this is expressed differently in each twin. Another example is cloning with animals. When a cloned animal grows it is not actually identical to the animal it was cloned from, and again that’s because the two animals share the same DNA but don’t express their genetic material in the same way.

What’s the role of the epigenome?

The epigenome is responsible for making sure the nerve cells in our brain produce the chemicals they need to transmit signals or that the muscle cells in our heart beat as they should. It also protects our DNA by inhibiting exogenous sequences, meaning threats that come from outside our organism. So the epigenome is closely tied to the way our body works, chemically and physically, and also defines us as a species. Remember, for example, that humans and chimpanzees share 99.9% of the genome but have different epigenomes. And finally, the epigenome is also dynamic, meaning that it is characterized by constant change and can be modified by external factors. For example, we know that tobacco consumption, excessive alcohol consumption or over-exposure to solar ultraviolet radiation modify the epigenome negatively, while physical exercise and a healthy lifestyle favour it.

Does the epigenome’s dynamic nature make it easier to work with than the genome?

It does. It’s very difficult to repair the mutation of a gene that causes an illness. If the mutation is an activating one, you can block it. But if it a loss of activity is involved, that’s more difficult to recover. On the other hand, because the epigenome is in a constant process of change this allows us to use drugs to reprogram the cell, helping it to remember, as it were, what its normal epigenome was like.

What can epigenetics tell us about ageing?

«At the end of our lives, it appears, we die with exactly the same genome we had at birth but our epigenome has altered»

Epigenetics and ageing are closely tied in many ways. At the end of our lives, it appears, we die with exactly the same genome we had at birth but our epigenome has altered. Studies of the brain show that the epigenome’s changes are fairly intense during the period between our birth and adolescence, that it stabilizes until we reach the age of 70, and that afterwards it starts to fluctuate again, this time entering a process of decline.

The most well known epigenetic mark is DNA methylation, where a methyl group—basically one carbon atom surrounded by three hydrogen atoms—is added to a particular point in the DNA sequence. We’ve compared groups of newborn children to people of 50 and 90 years old and seen that as people got older the epigenome gradually lost its methyl groups. And when that happened, the nervous system stopped working properly, the nerve cells didn’t produce neurotransmitters as they were meant to and the muscle cells in the heart didn’t beat regularly any more.

We reached the same conclusion in a study on a group of children with the genetic disorder progeria, which causes premature ageing, where we found that DNA methylation in children of eight was happening at the same pace as it does with adults aged 90. Because of their ageing epigenome these children had very little time left to live: basically, they were eight-year-olds with a biological age of 90.  Either way, maybe in the future epigenetics will help us make more reliable predictions about life expectancy.

Does that also mean we might eventually reverse the ageing process?

Apart from DNA methylation, another important conditioner of ageing is histones, which are the proteins that act like spools to wind up our DNA. The DNA in each human cell measures about two metres long and the histones are essential for wrapping it into structural units. We know that as we get older this packaging process becomes less efficient. We also know that by modifying the process we can extend the life span of organisms like worms and mice, or microorganisms like yeast species. We think that in the future certain drugs will be able to do the same thing with humans; and this will be important in the pharmaceutical industry because, obviously, people want to live longer. In fact, some of the cosmetics currently being marketed use substances that operate on histones.

Can groups of human beings share epigenetic traits?

Each of us is different from everyone else because we have a particular DNA sequence and epigenome. But yes, groups can share broader series of epigenetic traits. A study published by Genome Research showed that three different human groups had different epigenomes. Obviously, all three are identifiable as Homo sapiens sapiens, the sub-species of Homo sapiens that includes all modern humans; but additional marks help them adapt to their particular environment. Adaptation can take millions of years if it’s genetic but when it’s epigenetic things move much faster, and the change can be completed in just one or two generations. Epigenetics has also helped us confirm other theories of evolution, like the theory that modern humans originally came from the Horn of Africa.

So epigenetics helps us understand human evolution and the nature of certain illnesses. So far, the most widely studied illness is cancer. How has epigenetics contributed to this?

First we’ve proved that cancer cells experience an epigenetic alteration which stops them from recognizing themselves. In other words, a cell in the colon doesn’t recognize that it belongs in the colon; it behaves as if it were undifferentiated, meaning a cell that has not taken on any specific form or specialized function; and as such, it may do a number of different things, like attempt to move away from its location, invade neighbouring territories or metastasize. We’ve also discovered that certain genes that inhibit tumour growth stop working because the cell regulating this gene methylates, and the methylation blocks the gene.

Has the influence of epigenetics been seen in other illnesses apart from cancer?

«There’s an epigenetic factor in all age-related illnesses»

There’s an epigenetic factor in all age-related illnesses. For example, we recently learned that arteriosclerosis and some types of dementia involve epigenetic changes. We’ve signed an agreement with the Pasqual Maragall Foundation in Barcelona to study the volunteers in their ALFA programme, who are asymptomatic family members of people with Alzheimer’s disease. We know that in some families certain aggregations are not simply genetic because there’s no inherited gene mutation, which means that the change could be epigenetic. We’re also analysing what environmental factors do and whether certain epigenetic changes bring on dementia.

How long have epigenetic drugs been used to treat illnesses?

For about nine or ten years now. And they’re very efficient, especially in the treatment of leukemia and lymphomas. Now we want to use them to treat other kinds of tumours, like children’s tumours, and also lung, breast and colon cancer. It’s important to remember, though, that these illnesses are being effectively treated with other drugs and that in some cases epigenetic drugs may not turn out to be necessary. But in certain circumstances they could be very useful: one of the problems with cancer today comes when patients respond well to a treatment during the first two or three years but then the tumour reappears and has become resistant to the treatment.

Is that why cancers are more deadly the second time around?

Yes. Because when there’s cancer recurrence, the drugs you used to treat it the first time are no longer effective. Epigenetic drugs can help us treat tumours that reappear because the tumour still isn’t familiar with the new drug and is more sensitive to its effects. For example, we’re using these drugs to make chemoresistant tumours chemosensitive again.

Apart from helping to design specifically epigenetic drugs, can the study of the epigenome tell us whether conventional treatment will be effective?

We’ve learned we can predict the best treatment for a tumour by studying the individual’s epigenome. And that’s important because we avoid giving the patient a drug that won’t be effective or even a drug that will have negative effects. In fact, the first epigenetic marks predicting the body’s response to drugs are already being used to treat a type of tumour that starts in the glial cells in the brain.

So is epigenetics bringing us closer to what we call personalized medicine?

Definitely. In this day and age, we study a patient’s cancer at a molecular level. For example, in one quarter of the cases of lung cancer that we treat, we already have marks that allow us to prescribe drugs according to the changes we detect. That also goes for 20% of the cases of breast cancer and 70% of the cases of leukemia. But we still need to find marks for other kinds of tumours.

In the future, will we be able to map all the epigenetic marks in our DNA? If so, what will it mean for us?

We’re already beginning to map the first complete epigenomes, the DNA methylomes, and we’ve established these for certain human tumours and for some forms of dementia and arteriosclerosis. Of course one problem is that when there’s too much information we have to go back and discriminate between different kinds of data and understand them all, although computer programs can be very useful here. And another problem is that the process is expensive and so we need to keep investing in knowledge and research.

«We need to remember that discoveries happen because of funding and support in research»

But on the other hand, when I was a student only 45% of all cases breast cancers were cured and now that figure has risen to between 70% and 75%, which is a major improvement. And it’s thanks to the research in different fields, in medicine, biology, biochemistry, pharmacology, radiology, chemistry, physics and so on. If we look at the figures for breast cancer, every year the survival rate goes up by 2% to 2.5%. Sometimes we get tumours responding much better to treatment from just one year to the next, generally because we’ve made a discovery that allowed us to manufacture a specific drug. But if we want there to be more moments like this we need to remember that discoveries happen because of funding and support in research, whether public, private or social. Research has to be kept constant because breakthroughs don’t just come along by chance. It would be great if they did, of course, but that’s not the case; what makes all this progress possible is research.

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