Guillermo Oliver

Dr. Guillermo Oliver’s Laboratory focuses on understanding how each type of cell and organ acquires all its specific and unique morphological and functional characteristics during embryogenesis. His goal is to dissect the different cellular and molecular processes that make each organ unique and perfect. Dr. Oliver has participated in the Visiting Researcher Program of the Jesús Serra Foundation at the CNIC.

How did you find out about the Visiting Researcher Program of the Jesús Serra Foundation?

Thanks to my friendship with Miguel Torres, which dates back to 1992. We were together at the Max Planck Institute (Germany) and we maintained our friendship throughout the years, which has led us to collaborate on several different projects of mutual interest. The original idea was to come in 2021, but due to COVID it had to be postponed to 2022.

It has been a wonderful experience. I have interacted with many people with varied scientific interests and, in particular, I highlight my conversations with students and my participation in various institutional seminars and groups. For me it has been most satisfying, and I think for them too. And not only because we have addressed scientific issues, but more importantly other aspects related to the scientific career, the future of science in Spain, etc. I have been able to meet very committed students, but also others who are very fearful of future job possibilities.

Furthermore, I’m positive that my interactions with various groups at the CNIC will make future collaborations possible in the near future.

How has your relationship been with the students at the CNIC?

I’ve realized that the current generation of students is completely different from mine. I come from a small country, Uruguay, and when I was a student there were very few opportunities to do science, and I knew that I had to leave my country in order to be able to advance in my scientific career. Unfortunately, from my interactions with the students at CNIC, I have noticed that they face a lot of uncertainty when it comes to work options in the scientific field. Many of them are amazed by the fact that we have been able to maintain the passion for science despite all the difficulties that we have faced. Although they share this passion, they want to be able to balance it better with other important things in life. Their priorities are different. Where is the formula? They have asked me. Many of them don’t consider it a priority to leave Spain to do a Postdoc, because they think that if they go abroad, it will be very difficult, if not impossible, to get a stable job in the scientific field in Spain. And that worried me and made me sad. Undoubtedly, the CNIC has some of the best students in Spain. They are brilliant and I have been very impressed when speaking to them. But many of them have important doubts regarding the possibility of finding a job in Spain when they return, as well as the difficulties in obtaining funding.

Without a doubt, it is not easy to get a job in Spain, let’s be realistic, but it isn’t easy in any part of the world; the competition has been and will continue to be very hard. But what I tell them is to at least give themselves the chance, after 5 years of doing a PhD to do a Postdoc, if that’s what they want they should go for it, so they don’t regret it later. What I suggest is that they do a Postdoc and then decide. The Postdoc can be the best experience of their professional life. Some are hesitant and think about pursuing their career in the biotech and pharmaceutical industry. What industry? I tell them. In Spain it almost doesn’t exist. Also, I get the impression that many have a very naive concept of what it is to work in the industry. Very few are going to be the CEOS, and the truth is that the majority are just going to be “using a pipette.” And for that you don’t need a PhD. With this I do not mean to say that all of them should be scientists, but then, why did they spend 5 years doing a PhD? I am proud that I have convinced at least two who were very doubtful at first and are now going to do a Postdoc abroad.

“Undoubtedly, the CNIC has some of the best students in Spain. They are brilliant and I have been very impressed when speaking to them”

Which do you think are their main concerns?

There are many reasons: it is partly the country, partly the institution, and it is also the way the students themselves think about their future. Undoubtedly there is a cultural, economic issue, the fear of leaving family, friends, country since many still live with their parents. In Spain, as in my country, students don’t have the habit of leaving home when they start University, like in the USA. What is more, I think it might also have to do with comfort; perhaps some decided to start a PhD because it offered a decent salary but the passion needed to be a scientist was not there from the beginning. It is possible that mine and Miguel [Torres’] generation were very naive and the only thing that we cared about was the scientific passion; the rest, that is, getting a job and a decent salary came from a lot of effort and dedication. I understand when young people today want to have a more balanced personal and family life but unfortunately science is very selfish in that sense.

My suggestion to the students: if you don’t try, then you will always be in doubt. I am concerned about the fact that human capital as rich as that of the CNIC could be lost.

When Miguel [Torres] and I met, we both went with our families and we didn’t speak German. It was tough, but I wouldn’t change that experience for anything. I always say that the Postdoc experience is unique and it is the best moment of the academic period. As a student, you are a student; when you are a group leader, you have a lot of bureaucratic tasks, paperwork, which is horrible; but as a postdoc, it’s the only time in your life that you get paid to do what you love and you don’t have major responsibilities (sometimes a family). Furthermore, the future depends on you, on the effort, the hours that you dedicate to it is up to you, because it is for your future.

One problem that I have noticed at the CNIC is that there are very few foreign postdocs here, which surprises me, being it a first-class institution. I think that if the students were surrounded by foreign Postdoc students, they would have another vision. I can’t find any other explanation than that they are afraid of speaking Spanish. A center like the CNIC, and in Madrid, should be more than attractive for a postdoc.

When a doctoral student decides to go do a Postdoc, they are convinced that they want to succeed and that enthusiasm and persistence is contagious. In contrast, when you only have students with many doubts and who are negative about the scientific future, a current of pessimistic feedback is generated.

Many students have told me that they are stressed. And I ask them, is there any job where this doesn’t happen? Obviously, their vision of life is different, with an understandably greater balance between their personal and professional life; but if you have the passion to do science, you have to make an effort and find how to achieve that balance.

Coincidentally, during my stay, a group has been formed at CNIC to advise and interact with students.

Your group is a leader in embryonic development biology. In recent years there has been increasing talk of the possibility of regenerating the heart. How realistic is this line of work?

The dogma in the field of the heart is how to repair the heart after a heart attack. That is clearly the one-million-dollar question. We all know that the heart does not repair itself, in the sense that there is no proliferation of cardiomyocytes.

Many scientific groups are now working with stem cells as a way to generate new cardiomyocytes and induce proliferation. The problem with stem cells is that they can have unwanted side effects, as is well known.

Five or six years ago we began to have more knowledge about the lymphatic vasculature. It is known that, after a heart attack, the lymphatic vessels invade the affected region and their effect is that they protect the heart and improve cardiac function.

In 2020, we published in Nature magazine, a study that showed that lymphatic cells secrete factors, specifically in this case a protein called relin. This protein has a triple effect.

Firstly, during mouse embryonic development for the heart to grow to the normal size: when there is no relin, the heart is 1/3 smaller, which is an absolutely surprising result, because we never thought that the lymphatics could have that function.

“My suggestion to the students: if you don’t try, then you will always be in doubt. I am concerned about the fact that human capital as rich as that of the CNIC could be lost”

In addition, we saw that relin is also required for the regeneration and repair of the mouse heart. That is, it is important to help regeneration, very important for repair in adults after a heart attack. We have seen that if we put relin in the heart at the time of the heart attack, cardiac activity improves, and if we remove it, it worsens.

And, this occurs not because it improves the proliferation of cardiomyocytes, but because, in our case, what relin does is reduce cardiomyocyte death and decrease the infarcted area, and this consequently improved heart function. This does not mean that the lymphatics do not fulfill their traditional functions, like removing dead cells and circulating immune cells, but a very important function is to produce relin that reduces cell death and heart attacks. The question was - how are the new lymphatics formed? And that is what this new article that we recently published in The Journal of Clinical Investigation (JCI) explained, by showing that there is a protein, VEGFC, which is essential for stimulating the growth of the lymphatics, which is induced in macrophages when they trap cardiomyocytes, which are dying in the infarcted area. Those new lymphatics produce relin.

The important thing about this article was that it closed the circle. We now know that when there is heart damage, macrophages appear, which bring this VEGFC protein, and this protein causes the lymphatics to grow in the infarcted area, and these new lymphatics have a double function: to produce relin, which reduces cell death and the infarcted area, and on the other hand the classic immunological function that is to bring immune cells.

Additionally, we think that this occurs not only in the heart, but it is quite possible that this is a more generic function, because now there is more and more evidence that the lymphatic vessels have a beneficial or negative role in many heart diseases, in neurological diseases, Alzheimer’s, Parkinson’s or obesity.

Can this process be promoted? And if it is promoted, what effects will it have?

Yes, it can be promoted, although not in the way it has been done up to now, which is to use adenoviruses that are injected into the heart, since therapeutically it does not work and is risky. If there was a way to promote the growth of the lymphatics, it would have to be done with controls, due to the possible side effects. I don’t think promoting a limited growth of lymphatics would be adverse, quite the contrary.

We are now trying to determine the effect on the lymphatics in producing relin. However, the problem with producing relin is that it is too large a protein, so it cannot be packaged into viruses.

We have a mouse model that produces relin and we are following this line of research and we eventually want to move on to another model, more similar to humans, such as the pig.

On the other hand, we also have data linking the role of the metabolic part of the lymphatics, which is very important in myocardial infarction.

We have shown with a mitochondrial mutant that if you alter the metabolism of the lymphatics, it also somehow impacts the role of the lymphatics in improving cardiac activity. This is another one of the areas that we are following: trying to understand relin, lymphatics and metabolism, to see how they correlate.

As soon as we identify relin through proteomics we have about 30 possible molecules that could do the same thing in the heart or in many other organs. We have proof that the same thing will surely occur in the lung, kidney and liver.

The idea that the lymphatics have a role in the development of an organ and its protection was completely unexpected. It was expected from the blood vessels, but not from the lymphatics.

How do you rate your experience at the CNIC?

It’s been a crash course in cardiology in 3 months. During my stay at CNIC I have spoken with the ‘holy cows’ in the field of developmental biology and cardiology. In one way or another, they all work on the heart, but with different approaches: area of the immune system, more metabolic, more clinical. For me that has been very beneficial.

But on the other hand, it has generated many more doubts than I had before coming to Madrid. Now, I suddenly realize that I know a lot less than I thought.

My only frustration is not getting Postdoc students for my lab; I was sure I was going to convince someone to come to my lab in Chicago to help me with some of these projects.

Do you consider yourself to be a good mentor?

What I enjoy most about my career is being a mentor. I always say that it is like raising a child: if it goes badly, I suffer, if it goes well, I am happy. If you ask me what makes me proud, I would say it is when I am at a conference and the person presenting one of the talks has been a postdoc in my lab. I have a very good relationship with almost all the people who have passed through my laboratory for many years. We talk very often and we all learn from each other. And I realize that I am not the same today as I was 20 years ago.

In general, when I interview a person for a Postdoc, I am a bit obtuse. For me the key is why they want to come to my laboratory. It is essential that they come, not because they want a job, but because they chose my line of research and my laboratory.

And the second thing, is that they want to have their own group. If they tell me “Well, I don’t know if I want to continue in the university or in the industry or do something else”..., it’s not that I have anything against it because all the options are valid if one is satisfied with the choice, but to be a postdoc in my laboratory I prefer candidates who at least want to try to have their own research group, which will be a tremendous commitment on their part. Because the day I accept them, for 4 or 5 years I’m going to do everything possible for that person to do well, and I’m going to try my best to get them the best possible job. And that is a very serious commitment for me. I can’t promise you that you’re going to have your group, no, but I’m sure going to try.

My great pride is that 90% of the people who have passed through my laboratory today are successful team leaders around the world, and that is not a coincidence. I have tried to convince the CNIC students that they are going to come to a research area that is ‘hot’ and in which the chances of getting a job are very high, but I had no luck.

How would you assess the Visiting Researchers Program of the Jesús Serra Foundation?

The Jesús Serra Foundation scholarship has been exceptional. What I am most grateful for is for forcing me to make the decision to take a 3-month “break”. And that is very valuable. It is the first time in my career of more than 30 years that I have done it. Although the reality is that I have not taken it as a sabbatical and I have continued working in my laboratory, remotely. There have been many days that I have slept 3 or 4 hours. That has been the most strenuous part of the situation.

But despite this, I recommend it to all my colleagues. Seeing things from a slightly more distant perspective has helped me to think and reflect more calmly, without the daily pressure of being in the office.