Juan Pedro Bolaños is a biochemist and researcher in neuroscience specialised in neuroenergetics and metabolism. He is Professor of Biochemistry and Molecular Biology at the University of Salamanca. His research focusses on understanding the molecular mechanisms that regulate metabolism and redox homeostasis in cells of the central nervous system. Specifically, he studies the proteins and signalling pathways responsible for adaptation of neuronal metabolism to the continuous, high energy demands and antioxidants imposed by neurotransmission. He has received various awards throughout his scientific career, among which are the 2021 Castile and Leon Prize for Scientific and Technical Research and Innovation.

• Your work has focussed on the study of cerebral metabolism. What’s that got to do with cardiovascular disease?

The regulation mechanisms of the metabolism are, to a large extent, common to all tissues. What is explored in the brain can also be extrapolated, but with its peculiarities because there are important differences. What interests me is cerebral metabolism and knowing how the brain adapts to the different situations we face every day.
It’s understood that if we eat more fat, we are going to get fat and, if you do exercise, you lose weight. It seems we have everything well under control in terms of knowledge about how the metabolism regulates itself for the whole body, particularly in terms of adipose tissue. However, we know very little about how that directly affects the brain. What we intend to do is to attempt to understand what the adaptation mechanisms of neural cells are, I mean nerve cells, not just neurons. There are other cells called glial cells, for instance, astrocytes that have a unique morphological peculiarity, which is that they are the intersection between blood and the neuron. To explain this graphically, we could say that they are cells that hug onto the brain blood vessels, which is where they obtain nutrients, and on the other end of the same cell they are in direct functional, but not physical, contact with the synapsis.

And since Cajal we have known that the astrocytes must have, let’s say, a bridging mission between the composition of blood and function of the neuron. But this was not studied because we didn’t have the necessary technology.

The astrocyte is a type of neural cell that, as it does not have either synaptic or nerve activity, does not transmit impulses, but it does possess a very high metabolic dynamic, which means it can adapt itself metabolically, which in turn means that the biochemical reactions that take place in the cells can adapt on a large scale to very disparate conditions and survive. This does not happen in neurons, whose metabolism is a bit more rigid and more difficult to adapt.

And we don’t know why. Currently, in my laboratory in Salamanca, we are trying to understand how, through the chemical composition of blood, astrocytes are capable of sensing changes in lifestyle, for instance, diet, exercise, etc. For many years, I have been working to decipher what the main pathways are that regulate the metabolism in astrocytes, in neurons, to establish their differences in order to achieve a better understanding of them. Over the years, this has led me to the conclusion that astrocytes are enormously plastic from a metabolic point of view.

This plasticity, the quality to change metabolic substrate and precursor of energetic fuel, the quality they have to change from one to the other with hardly any apparent effects, does end up slightly altering the metabolic product.

The metabolism has a decomposition pathway of metabolites that is ultimately going to generate energy or produce other metabolic intermediaries which are released to the synapse, and which are used by neurons as, for instance, signals to regulate and modulate synaptic transmission, or even to obtain their own energy.

Without any doubt, these changes that simple astrocytes can undergo as a consequence of changes in lifestyle have an impact on neuronal activity.

My father was a pharmacist, and he had a clinical analysis laboratory, where I used to play. Instead of playing with chemistry set toys I had the real thing, made by my father, and I did all kinds of experiments

• Could we say that astrocytes are a possible therapeutic pathway for neurocognitive decline?

I don’t think we should lose sight of them.

• Why are you so interested in cerebral metabolism and specifically in astrocytes?

The truth is that sometimes you specialise in something by chance. I was in London doing my post-doc and we decided to cultivate the nervous system cells of a mouse, and we saw that it was easier to do it with astrocytes. Then I realised the potential of this line of research. At that time, I was studying the respiratory chain. We added a substance of nitric oxide, which is an important cardiovascular regulator, although we were more interested in nitric oxide as a regulator of mitochondria in the nervous system. Working with neurons and astrocytes, we added the same dose of nitric oxide, and we observed that the neurons died within minutes, whereas the astrocytes were happy. That also started to motivate me: I wanted to understand what differences exist between neuronal metabolism and that of astrocytes that allows them to adapt in such a different way.
Astrocytes adapt so well that, even with the respiratory chain blocked, without the cell’s main source of energy, the mitochondria survived.

• Like a kind of supercell?

That’s it, they are supercells. They are able to readapt their metabolism, obviously, changing other things, supplementing energy by obtaining it from different sources. That’s what readaptation is.
That capacity to resist attracted my attention. I wanted to know what makes them so resistant. Maybe what we have to do is find out how we can add these resistance mechanisms to neurons and maybe prevent neurodegeneration that way. That was more or less the idea I had at that time, but it turned out not to be so easy.

• Technology has advanced a lot since then.

Now we can quite easily answer questions that were almost impossible back then. I’m still answering questions I asked myself at that time. It is true that the field of cerebral metabolism is slightly less advanced than, say, cancer cell metabolism or that of cardiomyocytes, due to the intrinsic difficulty involved in working with a biological material of great complexity, where different types of cells take different metabolic pathways.

• Coming from a family of pharmacists, your path was clear.

I was certain from an early age that I liked pharmacology, I liked research. My father was a pharmacist, and he had a clinical analysis laboratory, where I used to play. Instead of playing with chemistry set toys I had the real thing, made by my father, and I did all kinds of experiment. It was a daily thing for me. And my father always encouraged me. He challenged me to think: do this, and why? he would say. My scientific vocation was unavoidable.

That’s where it all began. I went to study a degree in Pharmacology at Salamanca and did my PhD under the supervision of José María Medina, the biochemistry professor who has just retired. I went to London for the post-doc; I was there for two years and worked very hard. At that time, we could say that metabolism was an area of research that was of no great interest to anyone and, least of all, that of the nervous system, which was what I liked. During those two years I published three original papers that are, curiously, the most cited of my scientific career.

On my return to Spain, I did the competitive entrance exam for a teaching position at the University of Salamanca and, after passing, I applied for my first National Plan project. That’s when I created my group, without a penny to my name. I think it’s good to have a work-life balance. It’s true that before, research consumed you and it was much more difficult to devote yourself to research

• And suddenly you found yourself up against something you had no training for: leading a group.

Right. We often think we have a God-given understanding of how to do certain things. For instance, nowadays, for a National Plan project, you have to explain a series of things that are not just scientific. For instance, your approach to gender or how the data is going to be stored..., all of these aspects that we have no training for and don’t know how to tackle. And the people who assess you are people like me, who don’t have training in this field.

• How has the profile of a researcher in Spain changed since those times?

It’s more or less the same. There are people who know they want to research, whereas others, when they realise what it takes to get a tenured position in an institution, in terms of time, effort and sacrifice, decide they are not willing to make that sacrifice. Let’s say they are more practical. What I notice is that there are more and more practical people who prefer the pharmaceutical industry, etc. It’s not because they don’t want a career in research, but because they see the personal sacrifice as too great for what they will receive in return.

Science is very demanding. I think it’s good to have a work-life balance and it is true that before, research consumed you and it was much more difficult to devote yourself to research. Before, it was normal to work at the weekend or keep going until 12 o’clock at night. And you don’t see that anymore. Also, now, in some places you aren’t allowed to work at the weekend.

Juan Pedro Bolaños gave the seminar “Peculiarities of brain energy metabolism” at CNIC at the invitation of Dr. Mercedes Ricote

Again, this year, eight Spanish high school students with an average grade of 10 in both years of their baccalaureate course have received an ACÉRCATE programme grant, organised by the Spanish National Centre for Cardiovascular Research  (CNIC) under the auspices of the Young-CNIC Training Plan. This plan’s goal, a personal commitment of the centre’s general director, Dr Valentín Fuster, is to “attract and train the most brilliant young minds from the earliest age in order to create a pool of excellence in investigation in the field of cardiovascular research”.

The opportunity, open to all high school students in Spain, was awarded this year to 6 young women and 2 young men who met the requirements and applied to participate in the programme: 5 are from the community of Valencia, 2 from Madrid and 1 from Andalusia.

Including this year’s students, the total number of participants in the programme has been 120 students, 46 male and 74 female. In this edition, the eight young students are Jesús Bello Sancarlos, María Castellar García, Carmen Ferrer Martínez, Marta Garófano Liñán, Diego Montés Ferrer, Paula Nácher Zambrana, Lucía Sánchez and Carlota Zornoza Félix. In addition to participating in the day-to-day life of a centre of excellence in research like CNIC, they will be able to share their experiences and doubts with the centre’s research staff, but also with Dr Fuster.

Dr Fuster considers that staring a training programme during such early stages of education is the key to attracting future researchers, because young people are the “future of research in our country”.

This year, the students will attend presentations on scientific methods, as well as on basic, clinical and translational cardiovascular research. They will also have sessions with the Technical Units and Research Groups, where they will be able to do activities that help them come into contact with research, such as practical experience in molecular biology, transgenesis, shared medicine, histology proteomics, genomics, pluripotent stem cells, viral vectors, cytometry, bioinformatics , imaging technology, etc., and gain first-hand experience of the techniques used in research. They will also participate in a session and debate about women in science.

When the practical sessions end, the students will have to summarise what they have learned, propose a project and present it in public.

As well as coming into contact with the most cutting-edge technology and state-of-the-art experiments, the ACÉRCATE programme has a fun side. So, the participants will spend 15 days at a university residence, a foretaste of what awaits them in their university life. They will also complete a free-time programme including both fun and cultural activities.

Of all the CNIC training programmes, this is the one aimed at attracting the youngest talent. The continued support of the Fundación Pro CNIC is essential for the existence of this programme, year on year, and for it to continue attracting talent from an early age. “We are very satisfied with this concept, which we started more than 20 years ago”, adds Dr Fuster. He concludes, “in this way they get the research ‘bug’ and we encourage them to continue”.
 

GALERÍA DE FOTOS: https://www.flickr.com/photos/139407851@N06/albums/72177720310209659/with/53087643137/

The CNIC was one of four leading cardiovascular research centers in Europe featured in a live session within the official program of the European Society of Cardiology and its annual scientific meeting, ESC Congress 2020. The online meeting took place from 29 August to 1 September and attracted a record 115,000 registered delegates from a record 211 countries.

The other three featured centers, besides the CNIC, within this Leading Cardiovascular Research Centers in Europe series are the Oxford University, the Karolinska Institut in Stockholm and the Medical Center Hamburg-Eppendorf (UKE) in Hamburg.

The session included this video in which Valentín Fuster, CNIC Director General, Borja Ibáñez, CNIC Director of Clinical Research and Silvia Priori, CNIC Professor and Vice President of the European Society of Cardiology tour the cardiologists around the CNIC, its research and its training opportunities within the European cardiology context. You can watch the video from this link: CNIC in ESC.

//www.youtube.com/watch?v=MhSQREQm-ls&feature=youtu.be

Scientists of the National Center for Cardiovascular Research (CNIC) led by Rui Benedito have discovered a cellular and molecular mechanism that can be exploited to induce productive and sustained angiogenesis in tissues that have become ischemic due to reduced blood supply.

Until now, tissue regeneration treatments based on vascular growth factors have not succeeded in inducing effective angiogenesis—the process through which the body generates new blood vessels. The results, published in Nature Communications, suggest that it might be possible to manipulate the newly discovered mechanism to achieve optimal therapeutic angiogenesis.

Just as roads and highways connect cities and allow them to grow and operate, so the body’s blood vessels are essential for the development and function of tissues. Inhibition of vessel growth is an important therapeutic goal in cancer, whereas induction of angiogenesis has the potential to promote the formation of new blood vessels and tissue regeneration in cardiovascular disease.

Over the last 20 years, scientists have shown that appropriate growth of blood vessels in each tissue depends on a correct balance of several molecular proangiogenic and antiangiogenic mechanisms. Ischemic or hypoxic tissues secrete vascular endothelial growth factors (VEGF), which promote angiogenesis by inducing the proliferation and migration of vascular cells. Previous research by Rui Benedito’s group showed that blood vessel cells resist and oppose these external mitogenic cues through an intercellular ligand-receptor signaling mechanism called Notch.

The currently prevailing view is that increases in VEGF concentration or decreases in vascular Notch signaling stimulate both vascular cell proliferation and vessel growth. Therefore, strategies aimed at stimulating mitogenesis and angiogenesis to treat cardiovascular disease are based on drugs that promote VEGF signaling or block natural angiogenesis inhibitors such as Notch.

Using sophisticated genetic mouse models and cell imaging tools, Rui Benedito’s group have now discovered that the effect of these drugs and signalling mechanisms varies with the stage of angiogenesis and the vascular context.

The results in the Nature Communications study indicate that high mitogenic stimulation induced by VEGF (or Notch inhibition) arrests the proliferation of angiogenic vessels, while at the same time inducing the proliferation of more mature vessels, which are less important for effective angiogenesis in the context of disease. “The arrest of angiogenesis is due to a bell-shaped dose-response to the mitogenic stimulation. At high levels of mitogenic stimulus, the endothelial cells migrate and branch, but do not proliferate. Eventually, this affects the sustainable development of the blood vessels and the growth or regeneration of the surrounding tissues,” says Rui Benedito.

The newly identified mechanism could also explain the failure of several clinical trials seeking to boost angiogenesis in ischemic hearts after a myocardial infarction.

Rui Benedito says that the results “significantly increase our understanding of the biology of blood vessels and will enable us to design better therapeutic strategies to induce effective angiogenesis in injured or ischemic tissues.”

• Pontes-Quero, S., Fernandez-Chacon, M., Luo, W., Lunella, F. F., Casquero-Garcia, V., Garcia-Gonzalez, I., . . . Benedito, R. (2019). High mitogenic stimulation arrests angiogenesis. Nature Communications, 10(1), 2016. doi:10.1038/s41467-019-09875-7

One of the goals of the CNIC is to serve as a forum for the exchange of ideas in basic and translational cardiovascular research. To this aim, we organize every year advanced workshops - the CNIC Conferences –, to bring leading scientists together to discuss ‘hot’ topics of common interest. These conferences have a workshop format consisting of about 20 guest speakers and a limited number of participants (about 100). The participants will have the opportunity to present their work in poster sessions. This format enables an extensive discussion of current issues and controversies, and stimulates new thinking and ideas. The Conferences runs from Thursday late afternoon to Saturday lunchtime. 

The CNIC is organizing the next two CNIC Conferences:

2019 New Concepts on Age-Related Cardiovascular Disease - October 24-26. Organisers: V. Andrés, A. Hidalgo, JJ Fuster and A. Tall

2020 Cardiac Regeneration: from mechanisms to therapies - April 16-18. Organisers: M. Torres, N. Mercader, H. Sadek and M. Giacca

The first one, New Concepts on Age-Related Cardiovascular Disease, will cover four different topics of high relevance in the field: (1)  The Vascular-Neural-Immune axis in age-related diseases; (2) Somatic mutations and clonal hematopoiesis in cardiovascular disease; (3) The aging immune system in cardiovascular disease; (4) Cellular senescence and cardiovascular disease. The Conference will address the new trends in this area as well as potential strategies for exploiting this information therapeutically.

In the 2020 conference titled Cardiac Regeneration: from mechanisms to therapies, the mechanistic and physiological basis of cardiac regenerative ability will be extensively addressed from an evolutionary, developmental and physiological perspective.  The conference will include the latest advances in understanding the mechanisms underlying cardiac repair in naturally regenerating organisms and how can these be stimulated in non-regenerating mammals.  The conference will also review the current translational regenerative strategies, including gene therapy, modified nucleic acid administration, tissue engineering and cell reprogramming.  The forum will be an ideal setting for critically addressing the recent controversies in the field of cardiac stem cells and the failure so far in successful translation of experimental therapies into a clinical benefit.

More information soon at www.cnic-conference.com

The General Secretary of Scientific Coordination, Mr. Rafael Rodrigo, and the President of the Pro CNIC Foundation, Mr. Luis de Carlos, have formalized an agreement to renew the commitment acquired by the 12 private companies that constitute the Pro CNIC Foundation to continue participating in the National Center for Cardiovascular Research (CNIC), directed by Dr. Valentín Fuster, until the year 2028.

Thanks to this innovative example of public-private collaboration, the CNIC has established itself as a world leader in biomedical research. Hence, the CNIC has been awarded the Severo Ochoa accreditation in recognition of its international excellence in the field of research.

The Pro CNIC Foundation is an entity through which these 12 pioneering companies channel their contributions aimed at financing the CNIC, which has made it a benchmark for success in scientific patronage. In this Foundation we can find the solidarity interests of some of the most important companies in Spain: Acciona, Santander Bank, BBVA Bank, Endesa, Mapfre Foundation, Mutua Madrileña Foundation, Ramón Areces Foundation, Repsol Foundation, Inditex, "la Caixa", Prisa and Telefonica.

The patrons’ financing of the Pro CNIC Foundation enables the CNIC's research to have a direct impact on the care and improvement of the health of the general population. In addition, part of their innovations are converted into patents that generate an economic return and favor the development of R + D + I in Spain.

Three examples illustrate its contribution: On the one hand, the marketing of the polypill, developed by the CNIC, has already generated royalties of more than 1.5 million euros, making it the first drug approved in Europe for secondary cardiovascular prevention.

Cardiac imaging patent

Another example of translational research is the CNIC's new cardiac imaging patent, which has reduced magnetic resonance time from 40 minutes to less than one. This technology is essential to see the function and anatomy of the heart. The substantial reduction in time will have an important impact on the patient's well-being, the elimination of waiting lists and a more precise diagnosis for a larger number of patients. Finally, the biomarker for the diagnosis of acute myocarditis identified in the CNIC has allowed the development of a biosensor able to distinguish between acute myocarditis and a heart attack in only 30 minutes with a blood sample from the patient in order to be able to treat it adequately. The Pro CNIC joins together 12 of the most important companies in Spain: Acciona, Santander Bank, BBVA, Endesa, Mapfre Foundation, Mutua Madrileña Foundation, Ramón Areces Foundation, Repsol Foundation, Inditex, "la Caixa", Prisa and Telefónica.

Furthermore, thanks to the Pro CNIC Foundation it will be possible to continue to identify and train bright young people who show interest in science and research from early stages of their education and are already part of the quarry of researchers of excellence in our country.

In the words of Dr. Fuster, General Director of the CNIC, "this innovative public-private financing formula of the CNIC, which thanks to this agreement will continue until 2028, will allow the CNIC to remain a world leader in cardiovascular research and whose benefits are transferred directly to the patient.” From the CNIC, the relationship with the institutions that make up the Pro CNIC Foundation is highly valued: "We have shown that this is an effective and sustainable formula that, in short, guarantees excellence in cardiovascular research, the only way to move forward in the fight against what is the leading cause of death in developed countries and that will soon be in the poorest regions too", explains Dr. Fuster.

Meanwhile, the Minister of Science, Innovation and Universities, Pedro Duque, has expressed his satisfaction about this new impulse so that the National Center for Cardiovascular Research continues to promote translational research of excellence for the benefit of the patient and society.

The President of the Pro CNIC Foundation, Mr. Luis de Carlos, has given special thanks to the patrons for their constant involvement in the project and for their contribution to cardiovascular research. By the end of 2028, the companies of the Pro CNIC Foundation will have contributed more than 90 million euros to the project. According to D. Luis de Carlos, "it is great news for our country that this group of companies extends its commitment demonstrating once again, through scientific patronage, its involvement with both R & D & I, essential for the competitiveness of our country, as well as with the substantial improvement of the quality of life of all Spaniards”.

It is interesting to highlight that, within this innovative model, these companies not only contribute funds, but also collaborate in the decision-making and organization of the center through their participation in the Board of Trustees (Mapfre Foundation, Santander Bank, Telefónica and "La Caixa” Bank Foundation) and the Delegate Committee of the CNIC (Mapfre Foundation and Telefónica).

El Mundo: Especial Centros de Investigación en España