Mariano Barbacid

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26-83Jordi Play

«Cancer will never be eradicated, because it is inherent to human beings.» Statements like this one by Mariano Barbacid (Madrid, 1949) will come as a blow for many. But that does not make this eminent biochemist and oncologist stop talking with great frankness when he refers to the disease. And no wonder. According to the World Health Organization, it affects one in three men and one in four women at some point in their lives. «Society has to know the truth. Cancer is very complex and we will never find a cure, but we are going to use every available weapon against it», adds this scientist, head of the experimental oncology group at the Spanish National Cancer Research Centre (CNIO).

Member of the prestigious National Academy of Sciences of the United States, Barbacid focused on the study of cancer after completing his doctorate in biochemistry, which happened, in a way, by chance. To explain this situation, this oncologist likes paraphrasing something mountaineers often say when asked why climbing this or that mountain. «They usually say that just because it was there. And something similar happened to me with this disease.» 

In 1982, the USA National Cancer Institute, managed to isolate an oncogene in a human tumour for the first time, a gene that can cause cancer while mutating. In 1998 he returned to Spain after twenty years researching in the United States and came back with the assignment of creating CNIO, which has become one of the top research centres in the world in over a decade. He ran it until 2011, when he decided to devote his time to research only. Professor Barbacid activated a pioneering network of tumour banks and designed an oncochip that enables us to unravel molecular alterations that cause a single cell to become cancerous. A few months ago he was awarded an honorary PhD by the University of Barcelona, ​​another distinction to include on his extensive list of awards and recognitions.

Society perceives that lately we are immersed in a cancer pandemic. More people are dying from the disease. Is it only a perception or is it a reality
Society needs to understand that cancer is inherent to our existence. This disease is nothing but the aging process of cells, particularly regarding the deterioration of the DNA replication mechanisms and repair. As we get older, part of our repair processes stop working and mutations increase exponentially from age fifty, sixty and especially seventy.

But young people also get cancer.
Some people are unlucky and, with fewer mutations although in critical genes, may develop cancer at age thirty, forty or fifty. Such mutations may also occur while an embryo is developing, which is the period in which cell division activity is higher, and then the child develops a paediatric tumour. Between ages 15 and 45 people are less likely to develop cancer, but no one is free from error.

Thanks to advances in biomedicine in the past thirty years, oncologists claim that two in three cancers are either cured or become chronic
There are more cancers than infectious diseases. Nobody confuses cholera with AIDS, the flu or polio. And yet, people talk about lung cancer in a generic sense, when there are small cell and non-small cell lung cancers. The only thing they have in common is that they appear in the lungs. Both communicators and scientists together have to make society understand that cancer is not just one disease and, therefore, there is no drug that cures cancer, but some forms of cancer. And today we can say that half of cancers are cured. And yes, there are cancers that are chronic, like chronic myelogenous leukaemia, whose name is self-explanatory. Also hormonal tumours that are oestrogen-dependent, such as breast cancer. But these are only a few. Pancreatic cancer, for example, cannot be cured. If one is fortunate enough and doctors find a small tumour in the pancreas while a patient is undergoing stomach surgery, they take it off and, given it has not yet spread, then, of course, pancreatic cancer can be cured. But pancreatic cancer patients rarely survive the disease for five years.

It increases survival rates, but mortality figures have hardly changed in the last half of a century. How can this paradox be explained
It is a very good question which people rarely verbalise. There is an explanation: when we talk about a five year cancer survival, it does not mean that a person cannot die later. I just lived the case of a friend with colon cancer, for whom I forecast a couple of years and he has lived for eight years through operations, treatments, etc. According to statistics, this person was cured because he survived for more than five years, but that does not mean he did not die from cancer. It seems illogical, but despite the fact that survival is increasing, the number of deaths remains the same.

What factors increase the chances of having cancer?
Three factors, mainly. Tobacco is the first one, which is decreasing in Western countries. The second one is the uncontrolled exposure to the sun, which is also decreasing because people are increasingly using sunscreen. The third one, and perhaps the most unknown one, is chronic damage. The tumour with the highest incidence in the world is hepatocellular carcinoma, a liver tumour. There is a chronic damage there, which is the hepatitis virus, which does not kill you but is chronic. A person with chronic pancreatitis is twenty times more likely to develop pancreatic cancer than any other healthy person.

And if we got rid of these three factors?
There would still be cancer, it is important that people be made aware of this. I am not trying to give bad news, but nonsmokers, people who do not sunbath and with no chronic damage can also develop cancer. A friend of my wife’s who was very healthy, a sporty man, had lung cancer and lived for six months at age 47. He had not smoked in his life! Fortunately, something like this happens to very few people, but you can be unlucky enough and the mutations we spoke of earlier become a very aggressive tumour.

Why is it so difficult to treat these mutations?
Well, now you are asking me to explain a failure… There are two fundamental problems. To begin with, these mutations occur in a gene affecting the protein expression, which changes its activity. However, the altered protein is virtually identical to the normal protein whose activity is essential for the proper functioning of the cell. My laboratory at the CNIO happens to work on this particular issue. We work with the so-called Ras proteins, which mutate when there is cancer. It is extremely difficult to find differences between normal and mutated proteins; therefore, it is initially very difficult to do anything to block one and not the other. And then we have the activity of this protein. In the lab we eliminated three Ras proteins or certain proteins on the Ras’ signaling pathway. And we have seen that mice, the animals we work with, are dying in less than fifteen days. The problem is that we are dealing with an enemy that is almost like the proteins that are essential for life. Hence, it is difficult to find a target we can inhibit almost at 90% without attacking healthy cells. 

 

«Society needs to understand that cancer is inherent to our existence»

 

«There are more cancers than infectious diseases. Nobody confuses cholera with AIDS. And yet, people talk about lung cancer in a generic sense»

«I am not trying to give bad news, but nonsmokers, people who do not sunbath and with no chronic damage can also develop cancer»

 

25-83Jordi Play  

«Chemotherapy is very effective. But now we are seeing that even drugs that have shown very good results in the treatment of tumours become ineffective after some time»


Despite advances in understanding the disease, chemotherapy, radiotherapy and surgery remain the most standardised treatments.
Yes, good old chemotherapy is very effective. But now we are seeing that even drugs that have shown very good results in the treatment of tumours become ineffective after some time, because people eventually develop a resistance. Tumour cells are evolving entities that change rapidly. Furthermore, the tumour itself is not a single tumour, but many. A cell begins to add up mutations and at a given moment different clones start mutating differently. When we do a biopsy of the tumour in a cancer patient, we extract a piece of the tumour and then we sequence its DNA. We are going to find a mutation in it, but it may well only be present in 30% of that tumour. Cancer is much more complex than we thought. We should, and in fact the possibility already exists thanks to new ultra-sequencing techniques, sequence the human genome of each patient and tumour, because then we would know all the mutations it has. Do you know how many mutations does a lung adenocarcinoma have on average?

100? 200? 500?
Around 30,000 in its genome. The four types of cancer that have more mutations are melanoma, lung adenocarcinoma and lung and bladder squamous carcinoma. And all four of them have an external mutational component: tobacco and sun exposure. And it is not a hypothesis, it is already documented. We have a very complex enemy, as if we had a different infection and a hundred viruses at a time. And it is important to make society aware of it. Hiding it would be like the current crisis: we lived happily because we did not know we were in the middle of one. We have to diffuse the enormous complexity of cancer, both scientists and the media.

Ultra- sequencing techniques enable us to know which mutations each tumour has. It is a first step.

Of course, that is basic. Now, it is only part of the equation. The fact that there is a mutation does not tell us how it works, let alone how to inhibit the mutated protein. I will use an analogy. It is as if I told you that there is a terrorist cell in Barcelona that will cause a problem and I give you the ID number of all people living in Barcelona. Among these numbers there are the terrorists’, but how do we identify them? We do not know where they live, or how they look like, when they are going to act … Regarding our work, the Ras signalling pathway has about fifteen or twenty kinases, which are molecules against which it is relatively non-complex to make an inhibitor. A selective inhibitor is more difficult, though. The problem is we do not know which of these kinases are crucial. The complexity of a cell is infinitely superior to sending a man to the moon. Intervening when the function of a cell is altered without affecting healthy cells is a very difficult challenge. I am a researcher, I do not see the cancer patient’s everyday life, but what I am sure of is that if a pancreatic tumour has at least twelve mutated pathways, if we attack it with one or two drugs we will get but a small profit. If we really want to cure the tumour, we have to tackle it from the twelve mutated pathways. But what is the problem, then? Drugs are toxic. If you add a drug that is well tolerated to another drug that is very well tolerated and yet another one, there will come a time when they are no longer tolerated. We will have to make an effort to design more specific drugs, and that is not going to be easy.

Not very good news for those suffering the disease
It may seem there is no room for hope, but what I mean to say is that the problem is very complex and it is not going to be solved in coming years, there is still much research to do. Sequencing genomes is a small first step, now we have to understand how it works and then find the necessary tools to inhibit these signalling pathways that have mutated.

In order to do this your experimental oncology group at CNIO have developed a new kind of mouse.
We use a new generation of genetically modified mice, developed in the last ten or twelve years. These animals are able to faithfully reproduce human pathology. We have focused on studying lung adenocarcinoma, induced by oncogene K-Ras, and also pancreatic ductal adenocarcinoma. We know that Ras is the protein that has mutated in both cases, but we do not know how to inhibit it. However, the Ras signalling pathway are kinases, which in theory we know how to block, but we do not know which one is the most important one. What have we done? We used mouse lines in which we removed that target genetically. So we had strains for all kinases and we studied what happens if we fully eliminate a target, whether the tumour persists or disappears. And so we validate each of these kinases and we see what target will be more therapeutically important. This will tell us against which targets, against which proteins, we must synthesise inhibitors and, in addition, it will tell us the results.

After twenty years of research in the USA, in 1998 you returned to Spain with the assignment of creating CNIO, which has soon ranked among the top research centres in the world

I am very happy to be back in Spain and of having had the opportunity to launch the CNIO. It is an opportunity that is within reach of very few people. I started from scratch and tried to implement a different model of management from what was usual in our country at the time. It is based on two premises: first, that the centre does not have civil service; employees do have stable contracts, but not lifelong permanent ones. And secondly, the centre manages its own budget. These were the two conditions I demanded for my return to Spain and they were accepted. In ten years, the CNIO was placed among the ten or twelve best in the world and that was something that had never happened before in the history of Spain.

You were elected member of the National Academy of Sciences of the United States, a privilege only a few Spaniards have had access to.
Yes, and I am very proud. It happened two years ago. I was elected member in the oncology, hematology and general medicine section. There are only sixteen foreigners and only five Spaniards in the Academy, including Margarita Salas, Andreu Mas-Colell, Juan Luis Arsuaga and myself. Now that is important. Some people say that entering the academy is really the most important thing for them because it is a peer recognition, they have to vote for you in order to get in. 

Cristina Sáez. Journalist, Barcelona.
© Mètode 83, 2014.

 

22-83Jordi Play

«It may seem there is no room for hope, but the problem is that cancer is very complex and won’t be solved in coming years»

 

«Both scientists and the mass media have to communicate the great complexity of cancer»

 

© Mètode 2014 - 83. Online only. The Digits of Science - Autumn 2014