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When you write a text or when you interview someone, you almost always start by introducing the main character in the story.

But, for the first time, I need to start at the end and say that when we meet the people behind a project and know who they are and the circumstances that surround them, then we actually admire them and respect them a lot more.

The hustle and bustle of the corridor at the Institute of Pharmacology and Neuroscience was palpable. Two or three people stood waiting for a short while and they all said they "only needed to see Mizé for a minute to take care of something". I smiled and thought it had nothing to do with me, but I quickly realised that "Mizé" is Professor Maria José Diógenes, particularly cherished by her research team and other staff members who passed by. "Mizé" was also responsible for collecting several contributions, in this case to buy a gift for Professor Ana Sebastião, who had recently celebrated her 60th birthday.

When I was finally sitting down and waiting for the Professor, who was dealing with dozens of issues whilst trying to find time for the interview, I noticed that her desk had two trophies - a Prize awarded by Santa Casa de Misericórdia and a frame with a picture of her two daughters, Lúcia and Francisca.

The researcher is also a professor of Pharmacology and Neuroscience at the Faculty of Medicine of the University of Lisbon.

She remembers that when she was a little girl and people asked her what she wanted to be when she grew up, she said that she was going to be a Scientist. For a long time, that answer was seen as a joke, because being a Scientist in a country with little prospects of professional growth, seemed like an illusion, but being a woman further emphasised the idea that it was like wishing to work on the moon.

Her brain always believed that she would study the brains of others.

The only thing she needed to do was chose the right course - Medicine or Pharmaceutical Sciences. Her reasoning was easy to explain - she wanted a course that offered her real career paths, should her passion for science fail. Perhaps because life keeps on showing her that nothing happens by chance, a justification she gives as a devout Catholic, she very narrowly failed to get into Medicine.

She completed her degree in Pharmaceutical Sciences at the Faculty of Pharmacy of the University of Lisbon and, as soon as she got the opportunity, in her second year, she started doing research, since she was one of the best students in a chair linked to Neuroscience - Histology. Dora Brites was the first Professor who challenged her to do research work. Still as a student, Maria José was assisting her Professor with Clinical Analyses and, simultaneously, starting her study on the brain, helping other Ph.D. students who were being supervised by her Professor to find answers to a number of questions.

The course allowed her to never lose sight of the brain and whenever the optional subjects enabled it, she kept following her path.

After finishing the first stage, by completing the course, she had to attend internships, first in a community pharmacy and then in a hospital pharmacy. It was in the second stage that he took advantage of the freedom to choose a hospital to go to the Júlio de Matos Hospital, where she had contact with the universe she wanted to study and gained access to drugs for brain diseases. She was only 22 years old.

Despite the fact that life doesn't always give us what we want when we want it and the lack of funds to start her research, Maria José Diógenes refused to stop working and, dealing with some anger and dissatisfaction, she took on her role as a pharmacist. But that would be temporary. In the beginning she actually liked it, but routine quickly dispelled her slight fascination. It took one year for the third edition of the Master's Degree in Neuroscience to open, and she applied for it. She got in.

Professor Alexandre Ribeiro was the course director. "I don't know how Professor Alexandre Ribeiro managed to understand that I liked Science so very, very much that he began considering the possibility of getting me to do my Master's thesis here at the Faculty (of Medicine of the University of Lisbon)."

Living in Setúbal, she tried to reconcile her life as a pharmacist with the Master's Degree, but she eventually gave in to her passion for Neuroscience and started working in the area full time, also thanks to a scholarship granted within the scope of the project led by Professor Alexandre Ribeiro. And so she began her thesis.

Then she received another scholarship, this time financed by the FCT (Foundation for Science and Technology) and inevitably pursued her Doctoral Studies. Not surprisingly, the themes of the two theses would converge into one, as a sequence of a work that "began with trying to understand the interaction behind the activation of very specific receptors - adenosine receptors -, which were able to induce the activation of other, very different receptors - (brain-derived neurotrophic factor. (BDNF) receptors the purpose was to understand whether the molecular interaction had some sort of functional match."

This was the first step, which lasted a year, the time required to complete a Master's thesis. This was followed by a work that would reflect the evolution into a Ph.D. thesis. Ultimately, the interaction between two BDNF receptors - adenosine A2A and TRKB (Tropomyosin receptor kinase B) was the one that kept buzzing in the dozens of questions that Maria José Diógenes asked herself throughout her scientific career.

Her life has two different lines that, curiously enough, are reflected in the two trophies that I saw on top of her desk and mentioned in the beginning. Her career and her daughters. There is a sparkle in her eyes when she talks about Science, but she has no doubts when it comes to the top priorities imposed by her brain and her heart. Lúcia, who is twelve years old and was born while she was working on her Ph.D., and Francisca, who is seven.

But let's return to BDNF, the protagonist of Maria José Diógenes' studies, focused on physiology rather than on pathology. Maria José Diógenes realized that she would focus, not only on Alzheimer's disease, but also on Rett syndrome.

Rett syndrome is a developmental disorder for which there is still no treatment, with malfunctions similar to those found in Alzheimer's disease.

Last year, Maria José Diógenes was awarded the Mantero Belard Prize in Neuroscience, from Santa casa da Misericórdia, in the amount of 200 thousand euros. Although there is currently no cure for Alzheimer's disease, the researcher, together with her team, intends to advance knowledge, test an innovative drug and study a new biomarker.

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Maria José: BDNF, this neurotrophic factor, is very important in the context of the disease, because there are many different diseases (both neurological and psychiatric), in which this neurotrophic factor has a deficient action. Alzheimer's disease is one of those cases and so, for me, it made perfect sense to study ways of promoting BDNF in this disease. The Santa Casa Prize was awarded within the scope of this line of research. I started studying the biological basis of the disease, also for Rett syndrome. Do you know why? Because at the root of Rett syndrome is the loss of the BDNF function, due to a genetic change that has nothing to do with BDNF. My Ph.D. was completely focused on studying ways of promoting BDNF and, suddenly, I found another disease in which there is a BDNF deficiency and that no one had ever followed the approach I studied. It all began in 2014, when I won an FCT project to start a research on Rett syndrome.

 

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Are there any prospects of a treatment for Rett syndrome?

Maria José: The pillars of research on this disease have been to restore the actions of the role played by the gene encoding the MECP2 (methyl CpG binding protein 2), reverse the loss of the effects of neutotrophic factors, namely BDNF and re-establish neurotransmitter systems that are in deficit. But there is still no effective therapeutic strategy. What is our current situation at the laboratory? When we started planning the project, a physician who was developing her Ph.D. in this area happened to join the laboratory. So, we combined our efforts and, together with a medical student who was in the GAPIC program, we started our research work. Currently I have a Ph.D. student - Catarina Lourenço, who was awarded a Ph.D. scholarship from the FCT - and a Master's Degree student - Jéssica Rosa - working in this project. At the end of 2017, we won an international project from the French Rett Syndrome Association, which allowed us to continue pursuing this work. We hope that the FCT will give us good news about a new funding, but we're still waiting.

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Let's go back to BDNF, which opened up a parallel line of research. You were awarded the (Santa Casa) Neuroscience prize for the work you are developing on Alzheimer's Disease, in which you are testing a new drug and a new biomarker.

Maria José: The BDNF is a neurotrophin included in a group of neurotrophic factors that is very important for the normal functioning of the brain. The BDNF activates receptors (TrkB) that, in turn, lead to the activation of signal transduction cascades that result in a series of actions. These actions are crucial for the functioning of the nervous system, in what regards the protection against neuronal death, differentiation and neuronal growth and synaptic plasticity phenomena. If there is deregulation in the action of the BDNF, its effects are compromised. This is what happens in Alzheimer's disease, but we did not know the mechanisms behind this deregulation. The results obtained by the Doctoral students André Jerónimo Santos and João Fonseca Gomes allowed us to find important clues. These clues led to the development of the research project that won the Santa Casa Neuroscience prize.

This project has three main pillars: 1) advancing knowledge on the pathophysiology of Alzheimer's disease; 2) studying a new pharmacological strategy created by us and 3) exploring a new biomarker for this neurodegenerative disease.

A few days ago, Maria José Diógenes completed her Aggregation Exam, the final step for those who want to become Full Professors, and is the expert chosen by the Infarmed to assess pharmacokinetic drugs.

She is now facing the mission of answering as many questions as possible about Alzheimer's disease and Rett syndrome and, in order to achieve that, she relies on a team that she proudly introduces, saying that without it and without those who have contributed in the past, the present would not exist" - Rita Belo (Ph.D. student); Catarina Lourenço (Ph.D. student); Jéssica Rosa (Master student); João Fonseca Gomes (Ph.D. student); Catarina Beatriz Ferreira (Ph.D. student); Sara Tanqueiro (Ph.D. student) and Tiago Rodrigues (MD).

And because the quest for knowledge is not hampered by the fatigue of the hardest moments, she is already exploring other pathologies, namely Schizophrenia, while never losing her focus on seeking to restore the actions of BDNF, the change common to all these diseases.

Some people who are close to the Professor tell me she will get very far and those who, like her, believe in God, know that she will get exactly as far as her tremendous perseverance will reach.

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Acknowledgement – The editorial team would like to thank Dr. Rita Aroeira for her invaluable collaboration in collecting the information and preparing the interview and for all the support provided during the entire process.

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Joana Sousa

Editorial Team