From his small office at the National Cancer Research Center (CNIO) in Madrid, Dr. Mariano Barbacid (Madrid, 73 years old) cheerfully admits that he is entering “his fourth cycle” of 24 years. In the first, he graduated from Complutense University (and received his PhD) and was the youngest research associate at CSIC at 24 years old. In 1974 he immigrated to the United States, where he began as a fellow and directed the Division of Oncology at the National Cancer Institute in Maryland. And at 48 he returned to Spain to take charge of the CNIO, which he admits only had to “lay the foundations”.
In 1982, Barbacid’s team isolated the first human oncogene and identified the first mutation responsible for causing human cancer. These were fundamental discoveries in establishing the molecular basis of this pathology. The Reverse Path, a documentary film produced by Mediapro on the initiative of the Hermanos Álvarez Quirós Foundation, sheds light on the career of the Spanish scientist, as well as other aspects such as the lack of funding or the dangers of pseudoscience. A personal testimony that will visit cities like Barcelona throughout 2023 (University of Barcelona, 26 June and Poliorama Theater, November 7); Madrid (Navacerrada Public Library, July 25); Stockholm (Cervantes Institute, August 28); Valencia (Caixa Forum, October 23) or Salamanca (Liceo Theater, November 30).
Questions. In The Reverse Path he claims that cancer and its mutations are inherent in life. Does this mean we can never say goodbye to cancer?
Answer. Not cancer. From what we can, and now we can say goodbye, means dying of cancer, which is not the same. Cancer is an accident and we cannot avoid the mutations that cause it; What we can do is prevent the development of cancer, for example by not smoking. And in the case of pancreatic cancer, you should catch it as soon as possible because if caught too late, it’s practically deadly.
The first thing is to avoid risks: chronic inflammation, sunburn, smoking… I’ve never smoked and my risk of developing lung cancer is lower than others, but that doesn’t make me safe. Second: early detection. And thirdly, when the cancer has already bloomed, it depends on the therapy. Obviously, the earlier it is detected, the less likely it is to metastasize and the easier it is to cure. If the cancer is localized, it is removed through surgery. The problem is that most cancers don’t raise an alert until they’ve spread.
Q The first documented case of cancer caused by an outside agent, as you recall from the documentary, was that of the London chimney sweep. They contracted scrotum cancer because they relieved themselves without washing their hands and the soot contained carcinogenic substances. External factors such as hygiene can be controlled, but what about internal factors? How can you protect yourself if the cancer shows no symptoms beforehand?
R You can take some preventive measures. I’ve been doing colonoscopies for a number of years, but of course that only applies to colon cancer. This is why early detection is so important, because there are many types of cancer that do not warn, such as pancreatic cancer: if it gives a signal, it is already too late, because the survival rate is only 5% up to five years. Today almost 70% of people are cured of cancer, but it depends a lot on the type of cancer.
And then the size of the tumor is also important in preventive medical check-ups: If you have lung cancer that is five centimeters in size, you can see it; but if it comes from you, no… Without falling into hypochondria, the point is to be a little careful, especially after 65: if you have breast cancer, touch your breast and see if you have lumps; Look for dark patches on the skin that are growing abnormally. These little things can save your life.
Q People talk about cancer, but in reality there are many different types of cancer.
R As a matter of fact. We speak of “cancer” in the singular, and that’s a linguistic problem we have because, for example, a sarcoma and a leukemia are not at all the same. They are different diseases and we put them in one pot. When someone says to me, “I’ve been diagnosed with cancer,” it doesn’t mean anything to me. About what? If it is prostate cancer, there is a 95 percent chance of dying from cancer, but not from that cancer. You’re going to die of something else. But if it comes from the pancreas…
Q How were your beginnings at the CNIO in 1998?
R In Spain we were completely isolated. Yes, we were in Madrid, but we could have been in the middle of the Gobi desert because there wasn’t much science here apart from the university. But for everyday use we needed the most basic techniques of molecular biology, from animal husbandry and the ability to generate genetically modified mice, to proteomics, genomics, confocal microscopy… A whole range of techniques it takes to have at hand. It wasn’t about going to the Autonomous University to be harmed.
Q What is Dr. Barbacid today?
R We are working on two tumors caused by the oncogene [gen implicado en el desarrollo tumoral] that we discovered in 1982, K-RAS, which is responsible for the initial mutation in 25% of lung tumors and 95% of pancreatic tumors. In other words, there will be no shortage of work. What we’re doing is using animal models: from the mid/late 90’s mouse embryonic totipotent cells were coming onto the market that you can use to modify the mouse genome and get an animal that you can then introduce the same mutations that Humans, including the K-RAS oncogene, are responsible for pancreatic or lung cancer.
It’s not something we invented, but we were among the first to put it into service. By introducing the exact mutation into the mouse genome, the process is much more natural since it is the mouse gene and not an exogenous one.
Q To what extent can the results be extrapolated to laboratory mice?
R There are two major differences: the mouse tumor is much smaller, so whoever kills the mouse would not harm you or me; and time: In the case of lung cancer, for example, it takes an average of 30 years from the start of smoking to the onset of the cancer. In our case, it takes about six months for the tumors to develop, while in mice the tumors are much less complex due to their speed and size.
If we cure lung or pancreatic cancer in a mouse, we are not naïve enough to think that we will also cure cancer in humans. However, since the mechanism of tumorigenesis is the same, although we have not yet found a treatment for K-RAS in humans, we anticipate that there will be an incidence. But the fact of the matter is that we discovered it in 1982 and the first drug wasn’t approved until 2021, almost 40 years later.
Q They confirm that in Spain there is no tradition of discovery or scientific contribution like in the United States, United Kingdom, Germany or France. Why is it like this?
R I believe that on the one hand the Spanish people live with their backs to science; He values scientists very much, but doesn’t care about them. And politicians don’t care. In other words, in Spain they don’t talk about science; It’s something that doesn’t matter. And if it doesn’t matter, then why invest in it? I don’t know of any politician who says, ‘We’re going to fund science because the countries that funded it are richer now.’ And I’m talking in general terms, not just cancer research.
In Spain, there is short-termism, because it is much cheaper to pay for a patent, a license than not to discover a drug, and besides, you have it the next day. In the United States, however, the wealth created by the pharmaceutical and biotechnology industries is enormous. Virtually nothing is generated in Spain as there is no initial investment culture.
Mariano Barbacid in the CNIO laboratory. Alvaro García
Q What is the problem of funding scientific research in Spain?
R At the moment we receive less financial support for projects from the ministry than in 2008. Spain was the country that reduced its investments in science and technology the most during the crisis years, while other countries decreased their GDP despite this reduction they increased. For example, in the United States, the National Cancer Institute doubled the value by gradually increasing it over a 15-year period, and here we halved it.
Here they said they would double it (today public funding is 0.6% of GDP and they have promised to increase it to 1.25% by 2030), but you have to separate the science from the money, digitization flows into it, which is very important, but not science. Of course they increased me by 9% last year.
Q In other countries, private investments in science are also significantly higher. What is happening in Spain?
R That there is no money; We are a poor country. In the United States you can see that this or that donated 100 million to Harvard. But who in Spain besides Mr. Amancio Ortega has 100 million? And when he spends 300 million on public health on top of that, they come and green him. But the fact is that in Spain there are very few people who can donate… La Caixa donates almost 600 million euros a year, although little of this goes to science. But of course everyone donates what they want.
I can’t complain, on the contrary, because the CRIS Foundation Against Cancer funds us, and does it very well, for pancreatic cancer research. But the thing is very punctual, and one cannot live on it.
Q How important was your time in the United States for your academic career?
R All! The question was what to work on. So everything was molecular work, but with oncogenes stuck in the viruses. Oncologists had no idea what caused cancer. I was fortunate that the first lecture I heard in the United States, in the spring of 1975, was given precisely by a French researcher, a postdoctoral fellow who came out of the lab of Mike Bishop and Harold Varmus. They discovered that these oncogenes were not actually genes from the virus, but genes (particularly from chicken) that had been rescued by the virus and had mutated and become oncogenes in the process. And then I asked myself: is it possible that human cancers could be due to the same oncogenes without a virus having to be involved, but rather by spontaneous mutation?
That stuck in my brain, but I didn’t know how to do it. And there I was fortunate to study with Ángel Pellicer, who was a postdoc at Columbia University in New York. And I saw that actually human cells had these genes that had to be cloned and then isolated. And from there came the RAS genes, the first human oncogenes that we published in 1982; and from there we explore how they work.
Q In “El camino inverso” you also talk about two important female references: Margarita Salas, who was your teacher, and your third year high school teacher, who sparked your calling and curiosity. Is there still a gender gap in research?
R Yes, for me Margarita was a reference, although she didn’t accept me as a PhD student (she laughs), she always reminded her of that. And then the teacher Carmen Michelena, who taught me in the third grade and instilled in me the virus of science. But aside from these anecdotal issues, to me men and women in a lab are exactly the same. Notice that now, for example, in my lab there is only one male, the rest are females. I had great co-workers and associates.
What is happening is that while there are more women, they are not in managerial positions such as laboratory managers. Here we have María Blasco, a female leader of the center, but two-thirds of the group leaders are still men. What you have to do is not to discriminate and be aware that you have to promote the role of women. But not because she is a woman, but because of her knowledge.
Q What treatments hold the future in the fight against cancer?
R The future lies in immunotherapy, in targeted therapies and in CAR-T cells, which are currently only found in hematopoietic tumors. And targeted therapies are only available for cancers where the mutation is known and there is a drug for it. But today, chemotherapy is probably used more than the other therapies combined because there are so many tumors and so many mutations that there are no drugs to treat.
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