“Sometimes we should put a brake on the curiosity of scientists”
Ana Zubiaga is a brilliant researcher and tireless worker. One of those who impregnates his great knowledge with a garment of humility. She has been awarded the Elhuyar Merit Prize of 2020, because she has been socializing all her life and everything she knows about genetics. We analyzed the genetic regulation of cancer and after 40 years we wanted to know how it understands the disease. It has also provided us with the concerns and dreams generated by genetics.
“Sometimes we should put a brake on the curiosity of scientists”
He has made a great effort to share information about genetics with the Basque society. Why?
From the beginning I saw that people had an interest in genetics, although sometimes I did not know how to ask questions. It gives work, but then it returns you a lot. Personally I have received a lot. When I go to the villages to give some talk, I find people interested and it gives me much satisfaction to satisfy their interest because I see them living the pleasure of knowledge. It's like music. What is it for listening to music? We do not know, but the pleasure that feels is great. This is also the awareness of the functioning of life.
Those who have learned in the laboratory with you speak of your role as mentor and how you have marked your scientific sense.
For me it is a great responsibility to have a work team. We are not at Harvard, we have no resources. But in the place where we find ourselves we can progress if we become faithful to ourselves. Our scientific questions are great, although we have no resources to get results as fast as they do.
He is a peasant from birth. How did your environment receive the desire to make a scientific journey?
I am a little outier. In the hamlet, the neighbor said to me: “Ana Mari, you always learning for teachers?” For him the highest level of learning was being a teacher, and he could not understand how he could be studying years and years for teachers. “When you finish, are you silly?” I laugh, but it is true that this is more difficult when you have no reference, as in my case. It is important to show about women.
You investigate the genetic regulation of diseases, cancer. What is the objective of your research?
My interest has always been to know how cells reproduce. The mechanism by which the cell knows when to divide, when it should remain motionless, when it should become a specialized cell, or when it will die. From there I came to cancer.
At Harvard we found that they cloned the transcription factor E2F1. Although it actually regulated the cell cycle, it seemed that it had some mutation and fostered the growth of cancer cells, that is, it functioned as oncogene. We saw him in our laboratory and began to investigate seriously: We created an E2F1 silenced mouse with genetic engineering, a knockout mouse, and then learned that physiologically it worked as a tumor suppressor. There my interest in oncogenes and tumor suppressors began.
Logically, E2F1 was not the only factor, eight have been identified in the family. When I returned to Euskal Herria I focused on the study of this family. And we have seen that some push forward the cell cycle, others stop it... It is now being studied how E2F1 and E2F2 prevent metastasis.
The way of understanding cancer and disease in general has changed a lot with the trajectory of genetics, right?
Yes, the path of genetics has always been like a roller coaster. Sometimes we've waited a lot for him, then frustration has arisen and then he's come up again… In the 90s he rose again and we started to understand diseases with genes. In other words, the indications of genetic determinism reemerged, again wanting to understand everything with genetics.
Genetics promised us that the sequencing of the human genome would preoccupy us with diseases, but has it not actually demonstrated a low prediction capacity?
Well, in rare diseases like Huntington's disease, etc., the basis of the disease is in the sequence of genes. They are clearly a consequence of a mutation. There are between 6,000 and 7,000 rare diseases. But it is true that in complex diseases, such as diabetes, cancer and the most frequent chronic diseases, it is not clear to what extent they have a genetic basis.
More than 100,000 genomes are already sequenced, many of them cancer genomes, but we still do not understand diseases. Once again, we have gotten into a decline in hope in genetics, since we have realized that behind most of the diseases there are many other factors, in addition to the mutations. We're still far from knowing it, but I'm sure there will be a time when we'll know to what extent genes condition.
Probably one of the biggest challenges of biology will be to understand the diseases as a whole, to clarify how they affect the expression of our genome the environment, the ways of life, the sport, the emotions, the pollution…
Yes, no doubt. Lately we are seeing that the genome is very aware of what happens around it. All these factors, our experiences, provoke epigenetic changes on our genes, that is, by placing a chemical mark they can condition which genes will be silenced or activated. Sometimes these brands can also be hereditary.
What happens is that we are only at the beginning. They can put many marks on the cromatine that until now neither imagined. Until recently it was thought that by methylation and acetylation genes and histones were marked, proteins that by winding stabilize the structure of the DNA. But there are many brands.
For example, the last discovery: lactilation. Lactate is a molecule that forms in the metabolism and have seen that it can mark histones. That means that metabolism also speaks with genes! In other words, the mediators that form in cell metabolism also influence the expression of genes. That surprised me.
In any case, the most difficult thing is to clarify the influence of emotions, since we do not know how this is reflected at molecular level. Little by little people will discover the cases and discover how it occurs in a molecular way. For example, how depression is related to immunosuppression and how this immunosuppression influences the subsequent development of diseases. But science still has no solid basis for saying many things.
And have drugs been created that change epigenetic marks?
Yes, there is some epigenetic drug. For example, the borinostate. It can change the epigenetic marks of histones and is used in the treatment of some cancers.
Lately it has been seen that the intestinal microbe not only helps us to digestion, but also commands in the expression of our genes, right?
Yes, that too! This is putting very interesting. They are two or three kilos of our body, right? And surely there will be virus. Well, besides helping in digestion, the bacteria are regulating other activities of our body from the intestine. We still know little, but suddenly we have realized that the microbiome is very active. There is a lot of interaction between us and our bacteria, also in the expression of our genes. It's amazing!
The problem is that we want to know more than we know.
Does science sometimes become too slow?
Yes, curiosity is huge and you have to satisfy it. But sometimes problems arise because we want to know everything right away, and that is dangerous.
Not only that, but genetics dance in slippery borders: human cloning, the genetic editing of the germinal lines… How does a genetic all this live?
All this we live very closely. He sees it as a non-scientist, but he lives it further. We are aware of its implications. The last one has been a genetic edition. When the CRISPR technique arose (6 years ago), from the beginning I realized that someone wanted to apply it to the embryos. Personally I was very afraid because I knew there are still many unanswered questions. Why? But there are scientists who want to press as much as possible the accelerator, I do not know very well why: for prestige, for money, for curiosity… In that sokatira lives science.
And is that genetics has given toy to human curiosity...
Yes, sometimes our curiosity has no limits. As I have come here, I want to go beyond, to see what I get. Always trying to prove where I can get there… It also has a point of narcissism. It is true that science has always worked like this, and from there many beneficial things have come, but I think many times we would have to stop.
And I'm also concerned about sequencing. Today is so cheap! In the US there is an initiative to sequence the genome of one million people, and in China, many others, in the UK 100,000… Within a few years we will know the genomes of millions of people and I fear that with this information we will not begin to classify and differentiate much more human groups, and I do not know if that is good.
What can we ask genetics in the future?
Look, I think the sequencing of cancer genomes will give interesting information.A year ago, in a great initiative, 11,000 genomes of cancer of different types were analyzed. And it has been important because they have sequenced the entire genome: not only the zones that encode proteins, but also the non-coding RNA. They believed that there could also be many mutations that cause cancer.The truth is that we still do not know what 99% of our genome is dedicated to. The dark matter of life is the one that should clarify genetics. For example, transposonies, genes that move place. They act as intracellular parasites, changing or shifting the genes around. They generate mutations and problems, but they will also tell us benefits, since we have not eliminated them throughout evolution. Transpoprobes account for 50% of our genome and we still do not know almost anything about them.
On the other hand, a question very related to epigenetics: we know what is the function of genes, but we have great gaps in the regulation of these genes. In fact, to know how a gene is regulated, for many years we have been studying its promoter, specifically the upstream zone. But we have realized that we have had a very reduced vision. In our genome there are many regions dispersed in chromatin and that are sending from afar how to regulate genes. This type of regulation will be the field on which it will be worked in the coming years. We have learned very well to sequence, but now we have to go on to understand the next level of complexity, to clarify how the entire genome — chromatin — moves and organizes in a harmonious way; how it guarantees the regulation of all genes, for example, so that some genes are on and others remain off at the same time. There we have a great challenge.
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