The great frontier now is the brain, the study of its genetics and epigenetics

With his eyes on the cells of the oldest woman in the world, the leader of the genetic study that seeks to find out what allows one to live so many years in an almost perfect state of health, the IJC researcher, ICREA professor and Professor of Genetics at the Faculty of Medicine of the University of Barcelona, Manel Esteller, emphasizes the convenience of also investing resources and efforts in biomedical brain research. "It is the last great frontier of research," he says. Three-dimensional genomics techniques already allow observing the molecular activity of the brain in vivo, and thus detecting alterations and behaviors of cells without touching them, in their natural space and in full operation. "This will mean another great qualitative leap for knowledge."

Last May, Manel Esteller was chosen as the best genetics researcher in Spain in the 2024 edition of the ranking of best scientists from the leading academic research platform Research.com. In addition, the researcher from Sant Boi de Llobregat also obtained position 37 among the 4,000 best scientists in the world who study human genetics.

---What has genetics told us, so far, about the diseases we suffer from?

---We know that only 10% of human pathology is strongly inherited. This happens, for example, with cancer. Only 10% of cancers are hereditary. It also happens in dementia diseases, where the strongly inherited represents 5% to a maximum of 10%, and in other diseases such as diabetes and cardiovascular diseases, too. In this 10%, you cannot escape suffering from them because you have inherited a mutated gene, a gene that is difficult to repair. In all the rest, there is an opportunity for intervention. And this intervention can be at a personal level and at a social level.

---Outside of that genetics so clearly determining in certain pathologies, what margin do we have in our hands to live longer and better? What depends on us and what doesn't?

---From a scientific point of view, there is a big question in research and biomedicine which is how much of what we are is determined by what comes from our parents, that which is more deterministic or inherited, and how much by what we do in our life, our attitude and habits. This is a discussion that is not closed. I like to believe that it is 50% what you inherit and 50% what you do. If your parents have blue eyes, you will probably have blue eyes too, it is very difficult to escape from that. But if your parents did not go to university, you can possibly change that.

---Placing ourselves in that 50% of possible intervention, given so much information about what is good and bad for our health, what do the studied diseases tell us we can do, individually, to avoid them?

---The maximum intervention has to do with toxic habits. We know that the main toxic habit, recognized by the WHO, is tobacco. It is a substance, a drug, highly addictive, so consumers are not to blame. It is very easy to start smoking, but very difficult to stop. Tobacco is associated with lung cancer, but also with so many other diseases that it is incredible. 90% of lung cancers occur in smokers. This does not mean that 90% of smokers get lung cancer. But they can have diseases that guarantee a very low quality of life, such as chronic obstructive pulmonary disease (COPD). They can suffer from cancer of the head, mouth, throat, and also bladder, because that is where the toxic substance is eliminated.

---In this, social intervention acts.

---The fact of having banned smoking in restaurants has helped a lot. But there are data that we need to know. Since women started consuming tobacco, lung cancers in women have increased. And this cancer kills more than breast cancer. And all this is due to a toxic substance. Tobacco is a very clear toxic substance. But also alcohol, although it is a socially accepted and more legal drug, affects the liver and causes cognitive disorders. We have seen it well in adopted children with fetal alcohol syndrome, who do not adapt at school.

---How does the consumption of toxic substances harm our body?

---Radiation, small metals, tobacco, alcohol, if consumption is maintained in the body for a long time, it first affects epigenetics. If genetics is our own alphabet, epigenetics would be grammar and spelling ---that which tells each gene how it has to express itself, what it has to do---. Toxins first affect functions, but then they come to change genetics, introduce mutations, break chromosomes.

---And from one generation to another, can not only genetic determinants but also epigenetic ones be inherited, depending on the life of the parents?

---It is inherited only if the acquired trait at the epigenetic level has affected a germ cell. If you break a bone or hit your head, this does not pass on to your children. But if the signal of an epigenetic change reaches the egg or sperm, yes. It is believed that this acquired signal only lasts three generations, unless it offers something good, then, at an evolutionary level, this is selected and remains. This occurs, for example, when there are chemical substances that affect reproductive organs, or when there has been a lot of hunger, and a nutrient is missing. All of this can end up affecting germ cells. Above all, it has to do with changing the chemistry of hormones and growth factors. Nothing more is known.

---Once we are clear about what we have to flee from ---toxins---, what do we know we do have to seek out?

---In the book The Secret of Eternal Life (Grijalbo), co-authored with Dr. Salvador Macip, we explain what we have learned in recent years in research on human aging. We have found about twelve cellular mechanisms that determine aging. These are properties of the cell that have to do with the cell membrane, what is inside, what comes to it from outside. All of this allows us to look at attitudes that lead to healthier aging, with the idea of adding more life to years and not more years to life. Because today what is happening is that people live longer, luckily, but, sometimes, the last years are lived with poor health and this is, among other things, an immense health expense. And it would be about dying older, but in perfect health.

"With research, we have managed to cure 65% of tumors; when I started my career, only between 5 and 10% could be cured, and this is increasing every year"

---Our super-grandma is in very good health. One day she will die and we won't know why. Well, she will have died of old age, because her cells will have divided too many times, she will no longer have strength, but she doesn't have a specific disease, she has small pathologies, but not a serious disease that will kill her. So, if we know the mechanisms that lead to aging better or worse, we can think of strategies.

---For example?

---Moderate physical exercise is associated with healthier aging. Exercising a little every day. And walking a little every day, half an hour, an hour, whatever each person can do, is apparently the best. Those who don't do any exercise, a sedentary lifestyle, the couch, this kills a lot. Also not getting out of bed. We have seen that elderly people who don't get out of bed die within a year. Extreme sports are also associated with premature aging. Excessive radiation should also be avoided, whether solar or from medical tests, such as chest X-rays or radiographs: only the necessary ones should be done, not ten a year, but those that are due. Just like sunbathing, we can't always be in the shade, because we need the vitamins that the sun provides us but, like everything, with balance and moderation, like exercise.

---And it's in our hands, diet.

---Diet is surely the most complex thing, because we are not laboratory animals that can control exactly all the doses of what we eat. Here the key is to avoid fats as much as possible, because the cardiovascular disease that results is the silent killer, it is a very frequent disease. Also avoid ultra-processed meat, like frankfurters, and ultra-processed sugars ---that very white chocolate---, because all this is associated with type 2 diabetes and obesity, which are other diseases associated with old age with a lot of morbidity.

---All this must be avoided. What should we eat?

---Fish, especially oily fish, because it provides us with lipids that are good fats for us. Let's remember that the humans who live the longest are the Japanese, and in part it's because of their diet rich in oily fish. In this sense, Maria Branyas is an exception, because she lives in Olot. Fruit is also recommended. The sugar we consume can perfectly come from fruit, we don't need to consume other sugar apart from that. Then we enter the world of legumes, lettuce, vegetables... If there is meat, white meat is preferable, and chicken would be the preferred choice. And all of this has to be in small quantities. The top experts say you have to stay a little hungry. We know that a little caloric restriction is associated with a bit of an advantage in survival. If you follow this balanced and varied diet, you don't need to take vitamin supplements, but you have to make sure you have everything in it: vitamins, protein, and lipids covered. Evidently, drinks with sweeteners, also out, because it's sugar.

---Where have we gotten in epigenetic research that is already being applied?

---In addition to understanding disease, epigenetics has had two clear applications. One is as a biomarker for tumor behavior. That is, when we have a certain altered epigenetics, we know that a tumor will be more aggressive, or more sensitive to a drug. From here, we can act to re-educate epigenetics. Today we have nine pure epigenetic drugs for patients. What these medicines do is reprogram cells to remember what their normal function was. That is, the function of a blood cell, a lymphocyte, is to defend us from aggressions, that's how the immune system works. The function of this cell is not to grow a lot, which is what happens in leukemia, but to grow when it's time, to defend us from a bacterium, a virus, whatever is needed. These new drugs restore epigenetic memory and are widely used for leukemias, lymphomas, and sarcomas, these types of tumors.

---How has Barcelona participated in all of this?

---Our laboratory, our cancer epigenetics team, was one of the first to preclinically design these drugs. We have been studying it for more than 26 years. And today there are already nine drugs approved in the world for use in patients. Apart from this, in Catalonia there are very good groups that investigate the basic mechanisms, to know what type of cell is altered, what type of modification, because in the epigenetic code there are many modifications. I believe that very good basic research is done here.

Esteller also investigates health and aging through the case of Maria Branyas, the resident of Olot recognized as the oldest person in the world

---If we think about photonics, we have one of the best institutes in the world, the Institute of Photonic Sciences (ICFO), led by Dr. Lluís Torner, it is world top. If we look at the economy, the Andreu Mas-Colell school, the Barcelona School of Economics (BSE), also makes a great contribution globally. But also the genomics studies that are being done in many hospitals here, and in our institute too, of genomics and epigenetics. If we look at clinical trials in oncology, we have centers considered among the best in the world. Vall d'Hebron Hospital is a world top center, with the newest clinical trials, with Dr. Josep Tabernero and his colleagues. That is to say, we are at a very high level, despite the few resources available. People are very imaginative with the few resources they have.

---What findings have marked a turning point in health research?

---In our laboratory's research, there have been several. The first was discovering that there were genes that described activity in cancer only through epigenetic mechanisms, without any alteration, no mutation, only epigenetics altered these genes and that caused cancer. This was in the late 90s when we discovered it. A second would be that, apart from discovering DNA alteration, epigenetics, there are proteins that are also altered epigenetically. We saw this between 2005 and 2007. Another important point was getting this knowledge to lead to clinical applications, such as biomarkers, this happened around 2000, when there was the first approval of an epigenetic test, in 2016, another, and later others. Finally, over time we also realize that things we saw in the laboratory that seemed very distant from patients, testing drugs in cells that we saw inhibited, that has served as a basis for drugs to be approved.

---It is the culmination of a beginning in the laboratory that closes a circle. From observation in patients, to application in them.

---We have not participated in clinical trials, which are more often carried out by doctors who work in the day-to-day of a hospital, but the drugs they are using are the ones we found to work. Our laboratory is on this frontier between people who investigate the most basic, most intimate mechanisms of epigenetics and those who give drugs to patients. We are in the middle, facilitating the flow of knowledge from one side to the other, and making discoveries that facilitate the transition from a fly to a patient. We do translational research, which is between basic and clinical.

---What is the relationship between epigenetics and somatization, the involuntary transformation of psychological problems into organic symptoms?

---There is a chemical relationship. Many things we do end up producing epigenetic changes, and this is especially related to hormonal changes. When we talk about behavior and other things, all of this produces discharges of hormones and neurotransmitters; for example, cortisol that arises with stress ends up changing epigenetics because it is a very powerful hormone, and it changes many things like eliminating anxiety. The same goes for other neurotransmitters in the brain, like dopamine, which make us more or less sad. All of this changes the epigenetic marks of neurons, or of the cells surrounding neurons.

---Therefore, it is interesting that research manages to access the brain.

---For us, mental health is one of the great frontiers, now the last great frontier is to do biomedical research on the brain. Because with cancer research, we have already managed to cure 65% of tumors, and when I started my career only 5 to 10% of cases could be cured, and this is increasing every year. Therefore, we are starting to turn the tide. In cardiovascular disease, with statins ---medications to reduce cholesterol---, physical exercise and diets, it is controlled, diabetes is not cured, but it has become a chronic disease; at least, people don't die from diabetes as they used to. But there are brain diseases for which there are no clear treatments. Dementias, whether Alzheimer's, or other types. And this is an area where a lot must be invested. The brain is the last frontier. The brain of neurodegenerative disease and the brain of neurodevelopmental disease, such as REET syndrome. With Alzheimer's, neurons die; with neurodevelopmental disease, they are dormant, they have not matured and, then, there are neurons that are poorly programmed, and these would be neuropsychiatric diseases, mental illness, which often has an onset after adolescence. And we have also studied this in the epigenetic field. We are not experts in it, but we have some findings in this regard. The great frontier now is the brain, the study of its genetics and epigenetics.

Esteller advocates looking at attitudes "to have healthier aging, with the idea of adding more life to years, and not more years to life"

---Now we are finishing the study of Maria Branyas to know how one can live 117 years and be in almost perfect health. I believe that after the summer we will have it. And now we are also very interested in being able to see the alterations of cells without breaking the cells, in space. Nowadays there are new techniques that allow us to see what is happening in a living brain. Before you had to take a brain and destroy it, just like a tumor. Nowadays there are genomics techniques in space, in three dimensions. This information can be very interesting because it is what is really happening to patients. It is very interesting to analyze all this and it will represent another qualitative leap for knowledge. The brain is a very difficult organ to study, because you cannot take a piece, you depend on brain banks, on people already dead, therefore, studying it live, without touching, looking at the molecules would be great. It would be to take to a molecular level what surgeons do today, who operate on a tumor while the patient plays the guitar and, when he stops playing, they stop, because it is an indicator. Well, this, at a molecular, cellular level, is one of the great frontiers today.

---Is that why the brain has been left for last?

---Yes, it has been left for last because it is very complex. The brain is a microcosm with many cell types, it is protected, we cannot take a sample, therefore, it is not simple. It is the irony of the organ that studies itself.