She is an Assistant Professor at the Faculty of Medicine of the University of Lisbon and a Neurosciences Researcher at the iMM. She also belongs to the Board of the Portuguese Society of Neurosciences.

Sara Xapelli studies the brain, that surprising organ that throughout life can continue to generate new neurons, showing that it can have plasticity. The Biologist by vocation - she is the biologist who likes to wear a gown, as she tells me laughing - she was born and graduated in Coimbra. Towards the end of the degree, when she was introduced to Neurosciences, she realized that it was a Professor she had during her Erasmus mobility, a specialist in Metabolism, who would mark her path, guaranteeing that she would be a researcher. From the initial struggle of having to learn how to do tests on animals, she realized that this sacrifice was a means for a greater cause, enabling better understanding of the human species.

She completed a Ph.D. in the field of epilepsy and in that period she moved between Portugal, Denmark and Canada. She says with a certain distant glance that these were the most enriching times in her professional life, but mainly at personal level. She will explain it to me later, as now it is too early.

When she returned to Portugal, she did a Post-Doc in Coimbra, focusing on stem cells. Her involvement in a group that was interested in Neurogenesis, i.e. in the formation of new neurons, and her participation in an international congress opened a door to her vast curiosity. She realized that it was thanks to a positive endogenous element in our body, the cannabinoids, that people felt sensations such as reward and satisfaction. These apparent evidences could be a path that made sense to those who studied Neurogenesis in-depth. The next ten years were spent studying this topic.

Cheerful and smiling, the empathic relationship she establishes easily makes her laugh when she recalls the time when she came to Lisbon to be with her husband, bringing with her two year old daughter.

She chose everything, the city, the Laboratory and Ana Sebastião, the Professor and Principal Investigator in Neurosciences and Deputy Director of the Faculty of Medicine. She becomes emotional when she speaks of Professor Ana, considering her to have provided her with the great change in her life. Joining a group like Ana Sebastião's would open doors for her to have her own research strand, and also teaching.

She fumbles and laughs while negotiating with her own feelings so that her emotions do not show. It is easy to understand the risks she took, since she has only recently obtained a stable contract. In 2016 she had the position of FCT researcher and since 2018 she has been an Assistant Professor, having lived on scholarships and one-off funding for each project she conducted until then. Would science be seductive enough in her life to keep her stuck with risk?

She was admitted and stayed. She has her own team, however, all members are funded by grants and experience the same sense of risk as Sara did in the past. She proposed a new research strand, which did not exist in the group, allowing it to explore its own doubts. "You know, I think that Professor Ana Sebastião is not even aware of the space she gave me and what changed me... now that I think about it", she tells me as if, for the first time and while taking a walk through memory lane, she discovered that the meaning of things is really discovered only sometime after everything is experienced.

From cannabinoids, she also started to study adenosine, Ana Sebastião’s chosen area and another molecule that plays a predominant role in Neurogenesis. She speaks about the team-work spirit experienced in the Laboratory, which belongs to the working group. Actually, it belongs to everyone, as that is the policy of sharing and helping each other. Currently, the research question she poses to herself and the working group is what is the relationship between the acquisition of new knowledge, during adulthood, and the formation of new neurons? Although the number of new neurons in humans is not unlimited, Sara Xapelli admits that brain regeneration exists and that it can be helped through stimuli or with the use of drugs.

She admits to being a perfectionist and says she doesn't like to make mistakes or not knowing the answer to something, for which reason she is always studying and attentive to her surroundings, as she doesn't want to fail people. This is also because when accumulating the role of Assistant Professor, she knows that she must always be one step ahead of what she teaches.

She got used to having graduate students and only in the last two years she started lecturing Pharmacology and Neuropharmacology to undergraduate students. She mentions the precious help of a Professor, also a researcher, who invited her to attend some of her theoretical-practical classes, when this very same Professor enters the room to say "good morning".

It's Maria José Diógenes, they have been friends since Sara Xapelli joined in. They have laboratory research that link them, but also the so often troubled role of mothers that brought them together in more difficult periods. She likes the informal atmosphere experienced at the iMM, a place where she has already made such strong friendships that makes her tell me that she has two families, the biological one and the laboratory group.

This Sara, who studies the brain and tries to decode it every day of her life, is the same one who manages two children, only with the help of her husband and without the presence of their parents in Lisbon. Everyone knows that on most days from 6 pm to 10 pm the role of mother is the predominant one, but after that, she resumes work, sacrificing daily hours of sleep. As she loves what he does, she recycles her soul strength to play all the roles without interfering with any.

She tells me that time teaches us to learn lessons and that brings me back to the times when she told me about Denmark and Canada. Some of the lessons have taken longer, but they set in when we take on new roles or new responsibilities. Now that she supervises Ph.D. students, she feels that only when we get older we feel the privilege of past experiences, valuing each detail much more than before.

 

She stresses that the comparison of experiences in other countries makes her value her own more, as well as the human resources she has and that, despite the scarce funding, if we are competitive in relation to the best laboratories in Europe, we owe it to the quality of the people.

In an era when we have already asked science when there will be an answer for the rejuvenation of our organs, it is now necessary to ask scientist Sara Xapelli if, despite its plasticity, the brain will be able to follow the progress of the rest of the body.

We already have cases of transplantation of some organs in medicine. Currently, nothing indicates that one day it will be possible to transplant brains. But even if it was possible, would Sara stop being Sara, becoming Sara.02 without the same identity?

Sara Xapelli: Let’s imagine that there was a brain transplant, the person would never be the same, only in science fiction, because memories, learning and experience could not be transferred. And even if they were, the person would cease to be the person we knew until then and would be someone else, the one who inhabited the old body. The brain has countless connections, at this moment it is impossible to reconnect them all.

 

Will we, one day, chemically be able to give inputs to the brain so that it lasts much longer?

Sara Xapelli: This is one of the great debates today in our area. We have two regions of the brain where there is a possibility of generating new neurons in the postnatal phase. These zones are the hippocampus and the subventricular zone, which, in humans, is closely related to the formation of new neurons in the striatum. The hippocampus is connected to learning and memory while the striatum is more linked to motor coordination. Right now, our group is interested in understanding if there are other areas of the brain where there are other neurogenic niches (where neurogenesis occurs from neural stem cells). However, we are aware that the number of stem cells is not enough to restore a major injury.

 

Such as Neurodegenerative Diseases?

Sara Xapelli: Yes, for example. Because in those cases, when they are diagnosed they are already at a very advanced stage. 

 

But let's return to the search for such niches...

Sara Xapelli: There are groups that have already tested brain stem cell transplantation in animal models, and more than forming new neurons, they also acted as a support, giving nutrients to that damaged brain area. What is interesting now is to try, without transplanting, to get the niches to make the cells divide and originate new neurons. For example, in the case of epilepsy, there is initially a large proliferation of cells in the hippocampus and then they tend to decrease because there is usage of the pool, with the new neurons making aberrant circuits promoting greater excitability.

On the other hand, it has been shown that despite the formation of new neurons, they end up dying because they fail to establish functional connections. We are therefore looking for drugs that can get these new cells to settle where there is damage and thus create functional connections without dying.

 

Why do they die?

Sara Xapelli: I would say that the main factor is the environment where the cells are, which is not favourable.

 

Let me make an analogy to see if I understand correctly. Is it as if we were trying to plant a tree on a completely burned ground?

Sara Xapelli: Yes. And even if that is the image, what we want is that, even if it takes longer, that tree can grow on burned ground. What is also important to know is that there are other types of cells that are very important and not just neurons. There are also glial cells, such as astrocytes or oligodendrocytes, the latter being responsible for the production of myelin sheaths, in the Central Nervous System, which line the axons of neurons and protect them. (These are lost in diseases like multiple sclerosis). What is important to mention in neural stem cells is that, depending on the stimuli, we are able to obtain different types of cells. This makes us use compounds such as cannabinoids and their derivatives, trying to obtain only positive results from them, and allowing them to serve as a stimulus. So as a first step we can do an in vitro experiment with cannabinoids, incubate the cells, and assess whether what we can get are neurons, oligodendrocytes or astrocytes.

 

And which take on different roles?

Sara Xapelli: We do not always want to produce more neurons, depending on the disease, we may want to extract different types of cells. Let me give you another example, in a stroke it's not just the neurons that die, it's all the cells that are there. What we intend to do is reproduce each type of cell, according to the needs.

 

Do you need to create the environment all over again?

Sara Xapelli: Exactly.

And you have been unable to find the answer?

Sara Xapelli: We have the experiments on mice. And one must be aware that the translation to humans afterwards may fail. In mice, we have to make several replicates to see if there is a standard effect, but a human has many derivations. We know that for almost every human being we would have to use a different stimulus. And that is why there is already a lot of talk about personalized medicine, where we can obtain the cells of the person, we test these cells in the laboratory and check if a drug can be effective. This part is no longer fiction and can become increasingly possible.

 

You said something very interesting in a recent interview to DN, which is that even in the current situation and not having all the answers yet, there is one thing that you know: it is that if there is a constant learning stimulus, at least some brain wear effects are delayed, which does not prevent Neurodegenerative Diseases, but can delay them.

Sara Xapelli: There is the Cognitive Reserve concept, mainly in Alzheimer's Disease, and one of the premises that is thought to be able to sustain this reserve is the hippocampal neurogenesis. Several studies made with animal models, show that: animals that have never left the same cage and have never been subject to environmental enrichment, have more long-term cognitive problems than those animals that are exposed to environmental enrichment. When I lecture, I always try to transpose it to the case of a person who has always been locked up in a basement, with someone who can leave the house, observe the world, read, exposing himself to various stimuli. And that even immediately raises the question of whether there are studies showing that people with higher literacy are less at risk to develop Alzheimer's Disease.

 

Is that last point proven?

Sara Xapelli: Various data show that people with higher literacy, even having Alzheimer's disease, have a slower progression of the disease. In addition, lifelong exposure to stimuli also appears to play a determining role. There can be several stimuli, the simple fact of listening to music, or maintaining physical activity, are stimuli for the brain. And the data supports this cognitive reserve issue. But on this issue we have a counterpoint, which is burnout and excess information. How will the brain behave then and there... It is a question that I raise for now with nothing to base myself on, but that makes me foresee some new approach in the future.

 

That is a big question. What happens to the brain when it receives excess stimulation and knowledge?

Sara Xapelli: We don't know yet, but I tell you about recent news regarding a researcher who ended up lost at an airport where he was making a stopover, because he no longer knew where he was. The amount of information he had and the things he had to do was so great that he had a burnout. It is possible to be connected 24 hours a day to information and to work. And in science, even if we wanted to spend 24 hours absorbing all the articles that come out, it would be impossible to be up to date with all the news. The amount of information that is available to us is impossible to control. And the use of the cell phone has aggravated this excess, if you notice how we barely use the phone for calls now.

 

And we still do not know the consequences of this simultaneous absorption of knowledge?

Sara Xapelli: No, we don't know yet. There is a saying that "knowledge does not occupy space", but it is not quite true, it does.

Is it an overload not of the computer, but of the brain?

Sara Xapelli: The volume of the brain does not increase visibly, but it is very plastic, and we already know that. We will at least have to “place” the memories “elsewhere” to be able to have other free storage spaces. We already have a certain memory defence which, by assimilating so much information at the same time, forgets the less important information.

 

The old age paradigm is changing. The World Health Organization says that until we are 65 we are young, we only enter middle age at 66. And only after 80 do we reach old age. A few days ago we heard Professor Carmo Fonseca talking about genetics and the strong likelihood that we will slow down the ageing of the body. And will the brain keep up with this rhythm?

Sara Xapelli: Excellent question, will the brain be able to keep up with the rhythm of the body... Remember our movie director Manoel de Oliveira as an example, or Professor Walter Osswald, who is 92 years old and has an extraordinary mind and gives talks of unmatched intelligence and lucidity. They are people who have remained so active that nothing has been left behind.

 

Does it mean that in terms of the brain we also have a paradigm shift? But it seems that there is an unbalanced equilibrium because we increasingly have more Neurodegenerative Diseases...

Sara Xapelli: We have because people in the past died before reaching the age of having these diseases, but as they live longer they are more prone to all neurodegenerative problems. It can be said that for now, the brain often does not keep pace with the body. But I continue to insist on the stimuli and the kind of life we lead. It is not by chance that we insist on the practice of physical exercise, care with food, but the lack of time makes us make a lot of mistakes. We have a lot of information, but we don’t use it due to lack of time. I have come to the conclusion that we live in a kind of "bubble". Mainly due to the environment we work in, we live close to a group of truly informed people. And very close to us there are many people who still don't have that much information and whose world remains very closed. The context marks people, but so does their mental health. In experimental terms, we could almost study two different groups of people due to the different stimuli and we would certainly conclude different things.

And with those stimuli, perhaps induced by drugs, could one rejuvenate the brain at the same pace as the body?

Far from being able to conclude these readings as if trying to read the future, perhaps one day the answers will be found.

For the time being, there is a certainty, stimuli will always act as prevention for cognitive problems, postponing the brain’s own validity and lucidity.

 

Joana Sousa

Editorial team