Alejo E. Rodríguez-Fraticelli was born in Argentina. In 2008, he moved to Madrid, where he studied biochemistry, and obtained his doctorate in developmental and cell biology from the Universidad Autónoma de Madrid in 2014. He subsequently moved to Boston (USA) to pursue work on cell fate determination in haematopoiesis at Harvard University and Boston Children’s Hospital. During his post-doctoral fellowship, Alejo Rodríguez-Fraticelli worked on developing methods for single cell lineage tracing in the haematopoietic system. His research has enabled him to establish a revolutionary way of connecting cellular states with cellular fates through clonal analysis to determine how variations in cellular states contribute to cell phenotypic heterogeneity. Since 2021, Alejo Rodríguez-Fraticelli has been group leader at the Instituto de Investigación Biomédica (IRB Barcelona) where he heads the Quantitative Stem Cell Dynamics laboratory. The staff on his team represent a diverse group with different ethnic backgrounds and philosophical approaches who have a passion for sharing resources and knowledge.
- Where does your interest in science come from?
I worked in the Hospital’s scientific area, which is internationally recognised for having started the treatment of paediatric cancer over 60 years ago. It is one of the best scientific environments to study something that seems fascinating to me, the origin of tumours and blood stem cells.
There are many cancers that originate in the blood cells but, when we began to study and understand the heterogeneity in haematopoietic cells, we realised that, in essence, this heterogeneity not only plays a role in cancer, but also has a part in all diseases: different types of immune and inflammatory diseases and even in cardiovascular diseases.
I believe that the work I did, which is what made it possible for me to set up my own research group, really highlights the fact that we need to understand biology from a new perspective: Instead of treating tissues, the cells of the tissues, as uniformly homogeneous populations that behave in a more or less uniform way, we have seen that this apparent uniformity is composed of a multiplicity of cellular behaviours that are highly defined and dominated by the origins of the cells themselves. This means that the cells that gave rise to these populations during their development have a great influence on their behaviour, response and, in many contexts, on disease.
This has opened our eyes, and now we are starting to understand this variation, which we all knew was there, but had put to one side. But now we have hit on one of the keys, which is that there is a highly intrinsic component to each of these cells, which is heritable and therefore propagates through cellular generations. When a cell divides, for instance, when we develop, and in the maintenance of our tissues, the daughter cells inherit characteristics that we have not fully determined, but which greatly define their functioning.
And although we have discovered it in blood, we believe this is probably valid for all of the cells in our organism, from the heart to the brain, liver, bones, etc. But due to the available tools, it is easier to apply to blood cells.
- So, the probability of having a disease is inherited through cell lineage?
It is completely possible that the only reason that a cell of mutates and causes a cancer in you, whereas for me it does not, is due to cell lineage. Obviously, there is a very strong component of other factors: environmental, genetic, etc… We know that there are many processes, but we had never thought of this as a defining factor. I think this will help explain many things about biology that we haven’t been able to explain so far. This is a growth field; at the moment there are 20 groups worldwide studying these things in this way, but there will be 100 of us by the end of the year, and thousands by the end of the decade.
In coming years, we will see therapies with modified immune cells to treat diseases from Alzheimer’s to heart or kidney diseases. There will be an explosion of immunotherapies precisely because they are well tolerated by our body
- So, the €1.5 million of European Research Council (ERC) funding you were awarded is for research along these lines?
We want to study whether ageing is really something we can foresee at cellular level and, therefore, treat.
- What treatment options would be possible?
And the other is with cell therapy, which means finding a way of modifying “aged” cells, maybe by extracting them from the organism and remodelling them, for instance, using gene or epigenetic therapy.
And, of course, the possibility also exists of not directly using haematopoietic cells but having cell therapy based on immunotherapy.
Immunotherapy has had great success in certain cancers; however, the main bottleneck when it comes to gaining approval for drugs is the risk that they may have for the patients who undergo treatment. The fact that so many cancer patients have been successfully treated with cell immunotherapy opens the door to applying these therapies as safe and tolerable for other types of disease. Many studies already exist, and in the coming years we will see therapies with modified immune cells to treat diseases from Alzheimer’s to heart or kidney diseases. There will be an explosion of immunotherapies precisely because they are well tolerated by our body.
- But maybe what companies and governments see is the cost of treatment for each patient??
That is the risk of cell therapies: not being able to achieve them fast enough in a scalable way. The main hurdle we need to overcome with cell therapies is that they are the patient’s own cells. And that brings problems: it is a slow process and more costly. If we could, like any other product, make them universal, they would be more accessible.
- Public hospitals already exist, like Barcelona’s Hospital Clínic, which have their own line of cell therapy. Can that make things easier?
I’m certain that within the next decade or two there will be many developments in this field, and in the delivery of drugs to specific sites. We tend to think that it has to be lymphocytes, the immune cells, which perform this function, but we can also reach other cells to secrete drugs that are useful wherever they are necessary. A lot of attention is being paid to this field, but obviously there is still a lot of science to do.
- Your work as a scientist is very aimed at clinical practice…
And for many of us, who lived this revolution at a time when we had to decide what we wanted to do, this caused a great impact, and my decision was very clear to me: this is the next great challenge for humanity for the next 100 years..
We have to create a much stronger theoretical basis because the science being practised is increasingly multidisciplinary. You can’t hope to reach a solution focusing exclusively on your microworld… things don’t work that way
- Why biology?
From that time on, and for me when I set up my own laboratory, it was essential to understand the consequences of those processes. Now we have more information, the objective is to find new treatments.
- You talk about the clinical application of your research. Do you think it is important to have worked in a hospital to understand the idea of translating basic science?
Until that time, I saw things in isolation, as if they were not part of a whole; there was academic science, and then there was translational science, which were two distinct things. And that experience made me see that it wasn’t like that; the patients were almost as involved as you, or even more so, in the molecular mechanisms, the biological bases, etc. and wanted to know exactly what was happening to their son, daughter, sister or mother. And that really opened my mind; there were not two different worlds, only a single continuum.
I think it is everybody’s obligation, but we need to explain it well. For a person like me, who never had a biomedical vocation, having taken that decision helped me refine my message, to know how to explain things to patients and tell them how what we are doing may someday be a solution.
What’s more, lots of these people don’t seek solutions just for themselves or their families, they don’t want it to happen to anyone else. At the end of the day, that is the hope behind everything we do.
- And does that in some way define the people that make up your group?
In my group, we try to compensate the disadvantages of the educational and academic system by contracting people from different disciplines to create a diverse, dynamic group. In my opinion, science is better that way, more productive in all aspects. And I’m not just talking about diversity of academic training, I mean different origins, cultures, nations and sexes. All of this generates a more diverse group that is more productive, has ideas that are more original and provides more exciting interactions that produce unexpected results.
- One of the aspects that some researchers who have visited CNIC mention is the very small number of foreign post-docs in Spain…
We have an immense population crisis; in 20 or 30 years more than half of the population will practically be at retirement age. There is an absolutely terrible crisis and if we don’t bring in international talent we will pay dearly.
- Is the new Science Law any help?
We need to bear in mind that before, science went more slowly. But now it is a race, a brutal race. Having, or not having, a patent worth multiple billions may entirely depend on whether that new machine on the market can be purchased next month or not until next year. This is what is completely changing the rules of the game. There is a lot of competition, and we need rules to be competitive.
Alejo Rodríguez-Fraticelli participated in the CNIC Seminar “Clonal determinants of blood stem cell heterogeneity,” at the invitation of Rui Benedito.