Mariano Barbacidis moving. Soon he will move his belongings to the new headquarters of theNational Cancer Research CenterHe has been directing since April 1998. That date already resonates as a key in his biography, hardened by triumphs outside of Spain. In 1982, he co-authored the discovery of the first human oncogene, ras, and has been on the most eminent brain runaway lists ever since.
Accepting the commission to set up the CNIO, possibly the jewel in the crown of current Spanish research, has helped people to recognize him on the street and to consider contributing to a radical change in the scientific structures of the country. Its first bombshell has come from the hand of biochips, computer structures for cancer diagnosis, which Barbacid wants to manufacture in Spain. Until now, its use is limited by the high costs of its purchase in the US market. It is the first contribution to the society of the center that he directs.
–But it won’t be the last …
-This is a key year for the CNIO, because, although there are already several activities underway, now we hope to give the definitive starting signal. In this new course, the work on the building that will house us will be completed, in what is known in Madrid as the Victoria Eugenia Hospital. It is expected to be completed in spring 2001.
–Once in the new house, all the research lines of the center will be definitively launched. Could you summarize them?
-Fundamentally, we work in two directions: a line of basic research and another of applied research. The basic will focus above all – although this will depend a lot on the resources that we may be able to attract towards the center – on the mechanisms of malignant transformation, what we know by the generic name of molecular oncology, and on the identification of genes. that to a greater or lesser extent are involved in the formation of cancer.
–Also in the so-called modifier genes?
-Of course, we will work on identifying genes that are directly responsible for the evil. But also in what we call modifying genes, that is, those that by themselves do not cause cancer but that make us more or less likely to develop it.
–These would be responsible for the fact that between two people exposed to the same risk factors, one develops cancer and the other does not.
-Exactly. We are in a totally virgin field of cancer research. Until now, there is no known gene in humans that by itself is not responsible for tumor development, but that becomes pernicious and has an incidence in the disease when it mutates other types of genes called oncongenes.
–And as for the lines of applied research?
-Here we have two great programs. The molecular pathology program is fundamentally a diagnostic program that is already underway. It aims to use biochips to establish a correlation between the expression patterns of tumors and their development and clinical behavior in order to identify their possible response to drugs. It is a very fruitful research area in the United States that we want to implement in Spain with the least possible delay.
The second project is dedicated to experimental therapies. That is, to the discovery of new drugs based not on their cytotoxic activity, like the traditional ones, but on molecular targets. At the CNIO we want to obtain drugs that are as selective as possible against the tumor cell.
–Faced with a project as expensive as this, society, which is the one who pays, demands results. Does applied research have enough weight in the CNIO?
-In this center, basic research will have the same weight as applied research. In fact, it will be one of the cancer research organizations in the world with the highest percentage of applied research. Normally, in European centers there is a trend towards basic and in the USA the applied is carried out by the pharmaceutical industry. In Spain we have very little industry, apart from the good but isolated example of Farmamar, so the CNIO has come to fill this gap. The drug search program will occupy 25 percent of our resources.
–Hopeful news about cancer continues to appear. But the truth is that the disease is still there and, in some of its manifestations, with a growing prevalence. What do we really know about her?
-20 years ago we started a glorious stage. The first oncogene was isolated in 1981 and published the following year; today we know more than 100 genes involved in the development of cancer. Of them, half are oncogenes and the other half are tumor suppressor genes or mutator genes. Every day we are learning more about the relationship between these genes. We know that they do not work in isolation, but are within a signal transmission frame.
The cell in the society in which it lives, that is, in the individual, is not selfish: before causing harm, it prefers to commit suicide by apoptosis. But when the genes that regulate this apoptosis fail, the cell becomes selfish, it does not want to die
–Is this how the tumor develops in the long run?
-Yes, apart from what we know as the mutator route, which is even easier to understand. It consists of the presence of repair genes that do not work and, therefore, accumulate mutations that either activate an oncogene or deactivate a gene that inhibits cell proliferation. All this we know in great detail.
–In enough detail to venture possible strategies to stop the process?
-That is our great challenge. But it is a very complicated step forward. It turns out that the differences between a tumor cell and a normal one are minimal, especially in their origins. It is not like an infection, where a virus or bacteria obviously modifies the cell. Here we are talking about our own proteins that act a little more when they induce cell proliferation or a little less when they are derived from suppressor genes.
So the tumor cell is not a completely differentiated agent that we can easily remove. Therapy consists of subtly manipulating processes that happen in the normal cell, but are unregulated. Finding specific inhibitors so that chemotherapy is effective and does not affect normal cells is very difficult.
–Neither is knowing exactly which agent causes cancer …
-We have our ideas that allow us to determine that there are external causes that are avoidable and other internal ones that, at least today, seem inevitable. Every time our cell divides, it has to copy a chain of 3,000 million units. The probabilities of error are not very high because otherwise we would have disappeared as a species, but there are. We cannot prevent errors in DNA replication, and when that error arises in a gene important for cell proliferation, there may be a spontaneous mutation against which nothing can be done. If human beings lived 150 years and there were no other causes of death, we would all end up suffering from cancer.
–But not all cancers are born this way, unfortunately.
-Not. There are external agents that can produce mutations. For example, the first occupational cancer was discovered among chimney sweeps in England and it was cancer of the scrotum. These men apparently touched each other with tar-covered hands, and the carcinogens in the soot penetrated through their skin.
Today, this cancer is practically eradicated from developed countries because the agents that produce it are already known. But, unfortunately, human beings sometimes do incomprehensible things.
–I know you are going to tell me about one of your favorite subjects … tobacco.
-Smoking is nothing more than self-harm. It is true that there are people who are more likely to develop a tumor than others. Not everyone who smokes a certain amount of tobacco for the same time has the same chances. But it is clear that some types of cancer, such as lung cancer, are almost exclusive to smokers. If today people stopped smoking in the world, in 20 years the decrease in cancer in ages under 70 would be spectacular.
The cancer that kills the most people, which is lung cancer, is totally preventable. How is it possible that a society that calls itself cultured is capable of injuring itself with this habit? This is something that among oncologists we cannot explain. Suffice it to say that the most effective way to fight cancer is to quit smoking. Much more than with any drug that can be discovered in 10 years.
–Do you have data to support the latter?
-The anti-smoking campaign in the US is already bearing fruit with a clear decrease in deaths. The death rate from lung cancer no longer increases there in men.
–There are other agents of whose malignancy we do not have enough information, such as electromagnetic radiation or mobile phones …
-All information about cancer appears published in magazines and the important thing is to look for those that really have prestige. Although sometimes, when dealing with experimental subjects, misinterpretations can be given. The two agents that nobody doubts are involved in the development of cancer in our society are tobacco and ultraviolet rays. In other societies, viruses are also prevalent, such as the papilloma virus in cervical cancer and the hepatitis virus in liver cancer.
As for other agents such as electromagnetic waves or mobile phones, there is still an open debate and we cannot say yes or no. Maybe we can never say. There are articles for and against electromagnetic waves, but the truth is that there is no clear evidence to say that they cause cancer.
–Not to say no
-The scientist is always very cautious when saying no because a negative result is not informative. But there is no information to the contrary. If we had to make an official statement we could say that there is no risk, but the scientist always has to be alert because what today seems like a no tomorrow becomes a yes.
–That caution also emerges when it comes to establishing a timetable to end cancer.
-Very rarely have you heard a serious scientist make a prediction about that. You cannot give dates, you have to continue working and expectations should be limited to saying that there is this new gene or this therapeutic possibility, nothing more.
–But do they consider cancer to be an eradicable disease?
-Yes in the cases in which we have identified the agent that causes it. Cancer as a long-term disease may be treatable but not eradicable. These are errors in our own genome, it is intrinsic to living beings.
–With what realistic objective should be worked then?
-We want to achieve that it can be lived with, that it can survive many years after its appearance and that all tumors are innocuous.
–What developments are expected in the field of therapy?
-The main treatment will continue to be surgery: it is the only way through which we can speak of a cure with a capital letter. When the cancer is spread, it is necessary to go to other treatments such as radiotherapy and chemotherapy. This is where we can expect news.
–In what sense?
-Radiation therapy is increasingly accurate thanks to computer science, which allows targeting only the diseased cell. In theory radiation therapy could heal without the help of surgery. But its application also kills the healthy organ. The same thing happens in chemo. Today’s drugs have a very small therapeutic window (the difference between the dose at which it does nothing and the dose at which it is harmful).
The challenge, then, is not to look for more powerful compounds, but more selective ones. We are confident that by making inhibitors against well-defined molecular targets we will succeed.
–Honestly, has gene therapy failed?
-Not quite. What happened is that some information exaggerated its projection. I think the power of gene therapy has been frivolized. It is not going to be a panacea, but it is not in crisis. Those of us who have had our feet on the ground did not share the opinion 5 years ago that it was going to be miraculous, nor do we now think that it has failed.
–Another therapeutic avenue in trouble is that of angiogenesis inhibitory therapies. It seems that they do not finish curdling.
-It is a conceptually attractive idea, which has yet to be demonstrated and that we are going to study here at the CNIO. Its effectiveness is limited because not all tumors depend on the creation of new blood vessels.
–A project like that of the CNIO always goes to the rescue of budget items. And lately, they’ve given him some scare about it …
-I will not comment on anything on that subject until the budgets are debated in Parliament. So, we will see if the 3.2 billion that are needed for this year are there. I can only trust that a project created by the same ministry with the support of the Presidency of the Government will not be curtailed.
–What is clear is that a very clear will is needed on the part of the Administration. How much money does the Spanish State spend on cancer?
-In particular, I don’t know. Health spends 4.7 billion pesetas a year. You go for medicine, so something is up to cancer. Taking into account that this disease causes a third of deaths, it should be clear what percentage is dedicated to it.
–Do you think that Spain is already in a position to definitively increase its budget contribution to science?
– Without a doubt, it is a question of will and culture. But we don’t seem to believe it. We know that it is essential to spend 1 percent of the health budget on research and that is not yet fulfilled. Today Spain is in a situation that allows it to face more than enough the challenge of biomedical research.
–A very expensive challenge?
-Absolutely. Biomedicine is pretty cheap. In other types of research, only the devices are more expensive … The normal thing is that a device for our purposes is worth less than 10 million, if it is worth 100 it already seems stratospheric. This investigation does not handle amounts that could affect state budgets, far from it.
–And are we also in a position to create an environment for escaped brains to return?
-Well, there are not as many as you think. In reality, there are few good researchers, what happens is that those who appear find little possibility to investigate and leave. In Spain we have lost a decade without creating new research centers to shelter them.
Jorge Mayor
This interview was published in November 2000, in number 234 of VERY Interesting.
