Embryonic development: “We think that any disturbance can have an effect” in the long term

“Biology can only be understood when we tell a story”, Elisa Gomez Perdiguero tells me at the start of our interview. Winner of the Impulscience® prize list from the Bettencourt Schueller Foundation for her work on fetal blood cells, the researcher opens the doors of her laboratory at the Pasteur Institute in Paris to tell us, with subtlety, the scope of her research.

Why Doctor: How did you become interested in the links between the disruption of blood and immune cells produced in the fetus and certain diseases that develop later in life?

Elisa Gomez Perdiguero: Originally, it was a personal story that motivated me. I lost my mother very young to cancer so I really wanted to work in cancer research. What interested me was the recurrences: what makes it so that following a very aggressive treatment of radiotherapy or chemotherapy, there is still a return of tumor growth which is, in addition, much more aggressive? At the time, at the beginning of the 2000s, the lack of oxygen – hypoxia – was a very interesting avenue because in solid tumors, there are always cells on the periphery which are crushed, lacking oxygen. and therefore a little “dormant”; making radiotherapy and chemotherapy ineffective on them. Then following the treatment, these cells, once again under oxygen, wake up and leave. So during my thesis, my goal was to focus on: how do the cells that form blood vessels, which are very important for tumor growth, respond to the absence of oxygen? The goal was to find ways to target them, to do adjuvant therapy, combined with radiotherapy or conventional chemotherapy, and try to minimize this possibility of recurrence. I then looked at how blood vessels, in the absence of oxygen, develop, remodel and form. I found that there were macrophages – immune cells – which were always closely linked to these processes. Then, during my post-doctorate, with the idea of ​​better understanding these blood vessels, I wanted to study these “partners in crime” and their interactions. And so my love of macrophages was born.

Macrophages, first line of defense against attacks

What do macrophages do?

A macrophage is a cell of the innate immune system. These cells are the first line of defense against attacks of microbial origin or linked to physical or mechanical damage. There are two types:
– the macrophages residing in the tissues: they are present to ensure the maintenance of the tissue, by eating and digesting our old cells which die every day;
– the macrophages circulating in the blood and coming from the bone marrow: these are those which are called for help when there is an attack, such as for example a lesion on the skin or an infection. They can arrive in very large numbers and act very quickly.

With my team, we are more interested in the residents and we look at how they monitor their tissues and how they determine when should they call for help or when are they able to manage the situation themselves.

In your research, you focus on disturbances during embryonic development that could modify the formation of macrophages and thus be linked to certain diseases in adulthood… What diseases are we talking about?

There is not a specific disease but rather age-related diseases and chronic diseases. We are mainly interested in tissue repair defects and in particular fibrosis which is a real burden for our tissues as we age: these are fibroblasts which do too much, which makes the tissue very rigid. To understand, we can compare an infant who is injured to an elderly individual: the first will have “new” skin after a week, while the second will have a scar. Another example, when you have a cardiac arrest, the body’s first reaction is to create a plug of fibrosis to hold the heart so that it can continue to pump. But if this fibrosis remains too present in the organ, it causes muscle fatigue which can lead to what is called heart failure. This disease is a public health problem because it is poorly treated and people affected are continually short of breath.

The link with macrophages is that the residents responsible for repairing these tissues are no longer produced once they become adults. In fact, they are made during pregnancy, they are established in their tissue of residence and remain there, as far as we know, throughout life with more or less success depending on the diseases that each individual encounters.

Children born during periods of famine have a storage metabolism and will be more likely to develop diabetes, obesity and cardiovascular disease later in life.

And regarding disturbances during pregnancy, do you rather study external disturbances coming from an infection for example, or internal ones, which would be, among other things, linked to a genetic developmental anomaly?

It is believed that any disturbance can have an effect. For example, the best studied case is the effect of maternal diet on the future health of children: we know that if there are periods of deprivation or excess diet during pregnancy, this will change the way The body’s cells manage metabolism. Concretely, children born during periods of famine have a storage metabolism and will be more likely to develop diabetes, obesity and cardiovascular diseases later in life.

With my team, we chose to focus on external disturbances and internal anomalies, with a model for each. For external anomalies, we chose – mainly because of the importance of viral infections in recent years linked to the Covid pandemic – to focus on the consequences of a viral infection at the start of pregnancy. Why the beginning? Because it is already well established, in experimental models, that a viral infection in the last trimester of pregnancy can have consequences on brain development and has been associated with behavioral diseases such as schizophrenia, anxiety disorders, etc. So we are more interested in the first trimester, to understand how the mother’s response to an infection can affect the development of the embryo’s immune system. Does this have consequences in his future life? Is it positive or negative?

Then, for genetic anomalies, we would like to focus on genetic mutations during development. If they take place at the beginning of pregnancy or at the end of pregnancy, does that make any difference to the disease that will develop later? For example, we are interested in a disease that affects 10% of children with Down syndrome: transient myeloproliferative syndrome which is pre-leukemia. This disease is interesting to us because it develops in utero and often resolves spontaneously a few months after birth without knowing why. Then there is pediatric mastocytosis, a disease of mast cells which are innate cells involved in allergic reactions. In children, only the skin is affected and this often disappears at puberty; but when this disease develops in adults, it affects several organs at once. So we would like to better understand how these similar diseases arise during embryonic development.

Thanks to this program and the endowment, we will be able to do in five years what we would have done in fifteen years initially.

You are a winner of the Impulscience® prize list from the Bettencourt Schueller Foundation… How does this give you a boost in your research?

So it’s not just a helping hand! Thanks to this program and the endowment, we will be able to do in five years what we would have done in fifteen years initially. In fact, without it, we would have to make choices about what we study. The story would have been broken up like a small sausage, into small slices which make sense in themselves, but which we would have had to try to reconstruct little by little as a whole because we would not have had a global vision to understand this what’s happening.

I would also like to add that my entire team is the winner! Without the admirable work of everyone over the last few years, we would not have succeeded in having this idea nor the tools or the desire to put it into place. So it’s really the entire team that deserves recognition for this award because it’s all these people who generated the data to make these hypotheses and, above all, who will continue to carry out this project for a certain time.