Research and Advanced Education
Professor Susana Constantino - A researcher who wants to know if low and moderate doses of ionising radiation can promote cardiotoxicity
She says she is not inspired to speak as she usually does, because of the tiredness she feels and that is visible in her eyes. Words are hard to get out of her in the first few seconds of conversation, gaining the rhythmic beat that I already knew in her, where ideas thrive with an immense desire to create passion in others when it comes to Science.
Susana Constantino, Professor of Biochemistry at the Faculty of Medicine of the University of Lisbon and Researcher at the Cardiovascular Centre of the University of Lisbon (CCUL), is a natural born communicator and this is intrinsic to her, with or without fatigue.
She speaks of science with such passion that she explains that "there was not always good sense" when she spoke of her ways to research. An area so competitive that it is necessary to have some reservation in sharing information, nevertheless, she does not regret any scientific conversation held up to now.
"I will even interact with an ant if it has anything to teach me", she tells me. But she is not only a person who wants to learn with others. She is also a Teacher and tries to instil her thirst for knowledge in the students. Doing only research would not bring her enough accomplishment, because transmitting knowledge to others is almost a mission. Without presumption, she wants to be able to affect someone's life, as was done with her before, and her mother is perhaps the greatest reason for being a teacher. "The taste for teaching is in my genes, because my mother was a teacher in the 1st cycle of Basic Education, and the ability she had and still has to transmit knowledge is incredible. My mother was a maternal, but very professional role model to me. Teaching for her was playful, it was her who taught me to have a method of study."
She is, in fact, surrounded by excellent teachers who affected her life choices, "I recently met with my Biology teacher from grade 10 to 12. I was having lunch with my son Pedro, who died of embarrassment at seeing me speak with the teacher, but I went over to say hello and told her that I followed biology because I was immensely affected by the lessons she taught me; this teacher did not award good marks, she was extremely demanding."
The phone rings and in an attempt to silence it, she shows me the screen and explains that the children have certainly tampered with it as it no longer obeys her orders. She shows me the screen, and this is how I am introduced to eight-year-old Pedro, six-year-old Tiago and four-year-old Joana. A family initially difficult to create, it has been growing because life is always a gift and a blessing.
She cannot watch a movie without intervening in it. She needs to touch others in order to add value to Science. She has always learned from the most experienced and says she continues to need them to continue to grow. When she meets someone like Professor Manuela Fiúza, she knows that she will work alongside them next and many times more, an obstinacy of those who keep pursuing results, "I knew her, and I thought I would have to send her an email because we would without doubt have common interests".
Her area of action is Blood Vessels and consequently the endothelial cell (a cell which lines blood vessels). It is the vessels that connect her to the CCUL. "Our research has two focuses: one in the Oncology area, where the vessels are responsible for supplying nutrients and oxygen to the tumour cell contributing to its growth and formation of metastasis. We are convinced that if we could reduce the source of nutrients or the vehicle for the tumour to go to another area, the tumour would not develop in the same way. The other area of action is in diseases with vascular insufficiency, where if we were able to induce the formation of more vessels, we could find a therapeutic solution."
The Vascular Surgery Service, which is also part of the CCUL, joined Susana Constantino and together they began an exploratory clinical trial.
When she started her own research group in 2008, she tried to find a niche of her own and went on to address the biological effects caused by ionising radiation. Initially, she was interested by how Radiation could modulate blood vessels. In fact, she knew that research was already being done globally in this area, but she also knew that the focus of this research was on the tumorous bleed vessels and the "modulation of ionising radiation mostly in the tumour area". It was then that by interacting with the Radiotherapy Service and observing what was done to the cancer patient, she realised that the radiation impacted not only the tumour area, but also the healthy tissues surrounding the tumour, though in lower doses.
It was in these surrounding tissues that she developed her study material by looking at the sub-therapeutic doses of ionising radiation around the tumour.
The route taken to try to find answers was only possible by close collaboration with the Radiotherapy Service.
Isabel Monteiro Grilo was the Director of the Radiotherapy Service when she began, "a woman with a genuine interest for research. She allowed me to perform my research, opening the doors of the Service in such a way that allowed me to interact with the teams, giving us a pioneering advantage. After the departure of Prof. Isabel Monteiro Grillo, all the directors that the Department has had, like Dr. Marília Jorge or Dr. Filomena Pina, the current Director, share the same interest in research being certain that it will bring more knowledge to patient care. All the teams that are included in this service have been helping us in carrying out our work with a lot of rigour and quality".
By analysing the treatment plans made for the patients, Susana Constantino realised which tissues were exposed to sub-therapeutic doses. This allowed the development of different animal models, exposing them to the same doses to which the patients are exposed, observing afterwards the biological effect that this caused. "The collaboration with the Service is so close that it allows us to make a true investigation of translation and to be competitive worldwide".
The international community saw the viability and validity of the question of Susana Constantino and the first to affirm it was Marc Mareel.
But let's go back to the year 2008, the year in which she posed the question that would start her research. In that same year, she was invited to IPATIMUP, in Porto, where she met Marc Mareel, a Belgian researcher and radio-oncologist from the University of Ghent, who despite being retired would become a great mentor and a companion in this large journey. "I ran to Porto, just telling the family on the phone that I would get home really late, I had no children at the time and could do these things more easily, it was a unique opportunity. I listened to him about his vast research in the area of ionising radiation and modulating cells in the tumour area. At the end of the presentation he said that if he was young and if he could start his work, he would look at the effects that radiation has on the tissues surrounding the tumour area. He referred to the importance of understanding the effects of sub-therapeutic radiation on both tumour recurrence and metastasis. I was very enthusiastic. The end of his presentation coincided with the start of my research in that area, and Marc Mareel was the first to internationally recognise the importance of the questions that were being asked at our laboratory".
Until now a consultant for the Laboratory of Susana Constantino, Marc Mareel became very influential in the discussion of her research and the validation of experimental models. On the same day they met, they immediately exchanged emails with common matters of interest. Even today, and despite being increasingly sedimented in her research, she does not fail to consult her mentor on the various paths to follow.
We're speaking of mentors and that makes me think about the academic journey and whether she has followers in it. What do you look for in your students? Curiosity? Apathy?
Susana Constantino: (Laughs) I'm terrible, because when I see apathy, that student is in trouble as I will be focusing on them. I talk a lot directly at them and if necessary, I turn on some lights for the environment not to become too cosy. I'm capable of asking them questions about what was being said. I might even call upon that student who is almost asleep to ask him for help in changing the slides. As you can see, I try to engage the student, but I respect that not everyone enjoys the same things, especially if I see that it is chronic. But at least I know that it wasn't because I gave up early. Then there is the opposite, the student who really lives what they are listening to and then I realize I focus a lot on them, because that student gives me strength and motivation. I maintain a bond with these. This reminds me of a former student, André Rocha, who has already finished the Medicine course. He was my student in the first year of Medicine, in the practical classes of Biochemistry. The following year he applied for a short traineeship on laboratory research, only twenty hours. I welcomed him. Over time and through our interactions I started noticing his brilliant mind. He wanted to come to my Laboratory, and later he was responsible for a specific purpose in our research, which forced him to research and to move away from here to absorb more knowledge and to get in touch with other Professors from other Faculties. He was co-author on some of our articles and completed his Masters thesis with us. He is now in Switzerland working on his PhD with animal subjects, pursuing a fully translational research project in the area of Intensive Care. And for four years, at least, he will be focused on it full-time.
How many Andrés can you find in a Professor's life?
Susana Constantino: Andres ... (thinks a little) Andrés as bright as that, I found only that André. But we get a lot of people who come for internships and get the taste for research, or we meet them later at a Postgraduate course and they ask me to access the Laboratory. And that is extremely gratifying.
Or doctors who contact us because they would like to start developing research in the area in which we work. When we verified that low doses of ionising radiation promote the formation of blood vessels, we intended to see if this would also happen in a context of vascular ischaemia. At the very moment we intended to do so, a vascular surgeon, Dr. Augusto Ministro, came up to us and expressed his will to carry out some research. I keep saying that in life nothing happens by chance. Augusto started to collaborate with us, and he became a PhD student that I had the privilege of overseeing and that was extremely enriching for our work. Augusto allowed me to discuss Science and do it in a perfect translation with the Clinic. We developed an animal model of lower limb ischaemia with him, and we have demonstrated that low doses of ionising radiation may be a therapeutic tool for inducing new blood vessels, an innovative and non-invasive tool. But we went even further and began a phase 1 clinical trial, in which we are studying the effect of these same low doses of ionising radiation on patients with critical limb ischaemia, patients whose only therapeutic option is amputation. I'm using this to explain to you that if there had not been an André and an Augusto, then I would not be who I am from a scientific point of view. While we were developing this work, I decided to join the CCUL because partnership work in the vascular area was already being done and it made perfect sense to look for new challenges in the cardiovascular area.
Our meeting arose from a suggestion by Professor Fausto Pinto, who mentioned the importance of your research for the cardiovascular area. Do you wish to explain how the connection with Cardiology was created?
Susana Constantino: The connection with cardiology and with the heart soon followed when we received funding to develop a European Project, the Horizon 2020 Project titled MEDIRAD, where we tried to understand the biological effects that low and moderate doses of ionising radiation have on the heart, particularly in the blood vessels. This question exists because there are human hearts (not the whole heart but a certain volume of the heart) that are exposed to these doses that we intend to study. These are the hearts of women with breast cancer, since part of their heart is exposed to these doses of radiation during radiation therapy for the breast. When I was involved in the writing of this project to be submitted for funding, we decided with other European groups to simultaneously propose a clinical study in which we would meet breast cancer patients in order to answer the same question. This is the reason why the now funded study has two strands: an experimental study using animal models and a clinic where we intend to study the effects on patients to be able to prevent some form of cardiotoxicity in the future, if it makes sense.
For this reason, the cardiologist and cardio-oncology consultant Professor Manuela Fiuza is leading this clinical study while we coordinate the research.
In this European and multidisciplinary task, it is up to our team to analyse the heart of the animal model exposed to radiation doses. Other groups will analyse other steps of the same sequence of questions and thoughts. Of the thirty-three Institutes, there are fourteen countries involved in a logical sequence of functions. But Italy, England, France, Holland and Portugal are groups that collaborate and are dedicated to the development of the animal model and later analysis of the heart.
What messages result from your research?
Susana Constantino: The main conclusion is that low doses of ionising radiation may induce the formation of blood vessels.
Radiation therapy has evolved immensely, allowing the levels of toxicity to be lower during treatment and that is an extraordinary achievement. The message we want to convey is that although the doses are low and do not cause toxicity, we must know their biological effects in non-tumour tissues and take them into account in the treatment of cancer disease. The other message is innovative and promising for patients with critical lower limb ischaemia who could benefit from blood vessel promotion using this non-invasive tool.
In the near future, we hope to attain a better understanding from the work we're developing on whether there is cardiotoxicity during breast cancer radiotherapy and whether we can indeed prevent it.
On a recent trip to Rome, where she presented her work at a meeting of the European project, she prepared her presentation during the flight.
When she has tasks or research in crucial stages and needs to develop them, she sets an alarm for 02:00 or 04:00 in the morning to get some work done before her children wake up. It's always Susana Constantino who takes them to school early, and it's almost always her who picks them up before the clock hits 6:00 p.m. She only stops granting her time to her three children when they fall asleep. Time may want to win the race, but she is stubborn in staying ahead.
Tiredness is as explainable as the pace at which she strives to discover what radiation causes to the body of a cancer or an ischaemic patient. In the midst of her ideas, her heart is eager to work and discover answers, so that patients may one day benefit from the questions that hopefully will have a good answer.
On a recent trip to Rome, where she presented her work at a meeting of the European project, she prepared her presentation during the flight.
When she has tasks or research in crucial stages and needs to develop them, she sets an alarm for 02:00 or 04:00 in the morning to get some work done before her children wake up. It's always Susana Constantino who takes them to school early, and it's almost always her who picks them up before the clock hits 6:00 p.m. She only stops granting her time to her three children when they fall asleep. Time may want to win the race, but she is stubborn in staying ahead.
Tiredness is as explainable as the pace at which she strives to discover what radiation causes to the body of a cancer or an ischaemic patient. In the midst of her ideas, her heart is eager to work and discover answers, so that patients may one day benefit from the questions that hopefully will have a good answer.
Joana Sousa
Editorial Team