Barcelona Metropolis

A certain amount of time elapses between the publication of a discovery and its application, but the fruits are eventually reaped. This is what has happened, for instance, in one of the major revolutions of recent years, immunotherapy in cancer treatment. When monoclonal antibodies were discovered, it was thought that many diseases could be cured rapidly and hundreds of companies were set up in the United States with million-dollar investments. Many of them went bankrupt and twenty years had to go by, but immunotherapy is now a reality.

Yes, I think so. Those first trials failed because, as a vector to alter DNA, viruses were used that went where they shouldn’t have gone. Now we are in a position to overcome those barriers. I am so convinced that I suggested to Carmen Vela, when she was Secretary of State [for Research, Development and Innovation], that there be a reference hospital for gene therapy in each autonomous community. It is not about sequencing millions of genomes, which is already being done, but about backing certain developments.

Although it is not a gene therapy per se, the Car-T technique developed by the Vall d’Hebron hospital to treat resistant lymphomata and types of leukaemia is very interesting. It consists of extracting lymphocytes from the patient’s own immune system and modifying them through genetic engineering. Once removed, they are inoculated with an antibody capable of recognising a specific marker in the patient’s tumour, so that when they are injected again, they are able to recognise the malignant cells and attack them. The therapy is very costly, roughly €40,000 per dose, I think, but is highly effective. When it works, the tumour is killed. Instead of treating the patient with exogenous molecules, such as chemotherapy, immunotherapy seeks to make the body itself eliminate the tumour.

CRISPR has been a critical breakthrough. It is an enzyme that, when nucleic acid is added, can recognise the specific location of the genome where the anomaly is found, cut it and, with the help of a virus that acts as a vector to introduce the normal gene, promote the exchange of pieces of DNA. That is the theory, but the technique is not one hundred per cent perfect: sometimes it can cut elsewhere, and sometimes, when cutting DNA, homologous recombination does not always occur.

Here we are entering a tricky terrain. From the ethical point of view, we have no problem treating somatic cells, because the effect of modification is limited to the actual patient. But if we touch the germline, the modification is transmitted to the offspring. From a technical point of view, there is no difference, but the consequences are very different. Imagine we can tell some parents: if we apply this gene to your child, he or she will never have cancer, but it must be done in the fertilised egg, which means that their children’s children won’t have cancer either. It would be hard to resist, but once it was done, a difference, a new class of humans, would be created. And even if there were consensus on not touching the germline, it would be difficult to prevent someone from doing so.

What we don’t know is what other consequences this modification may bear. This case shows that the problem is not mere speculation. The question is who can control what is done and how far can we go.

And all the more if the decision affects third parties. Can parents decide on genetic modifications in their children without the consent of those who will have to live with them?

In theory no, but we can’t guarantee it either. To select the sex, there would be no need to resort to embryonic selection. A sperm centrifugation using the Ficoll gradient would be suffice, as is done in livestock, which is a method that is one hundred per cent effective because X-bearing sperm weighs more than Y-bearing sperm. But just as five embryos in vitro are fertilised today for medical reasons, and then those with abnormalities are eliminated, the embryos could be selected based on other considerations.

Parameters such as height, intelligence or eye colour will not be easy to manipulate because these traits are spread across many genes. But it’s only a matter of time.

That is the crux of the matter. Leveraging the knowledge of genetics to avoid hereditary diseases or eliminate cancer is very desirable; but if only some people benefit while others are excluded, we are creating a major problem.

Those prices are only paid at the beginning. Sequencing the first genome cost millions and millions, and now yours can be sequenced for €500. Sequencing it is cheap. Getting it analysed is another matter. Ideally, all medicine should be personalised. There should be an artificial intelligence programme that, based on the genetic and physiological parameters of each person, could design a specific treatment. Will artificial intelligence take the place of doctors? Will doctors be psychological consultants? For the time being, more than towards personalised medicine we are heading towards stratified medicine, which entails grouping patients according to certain genetic traits and seeking the therapy that works best in each group.

We are working on a pulmonary bacterium that in immunocompromised hosts causes atypical pneumonia. We remove the pathogenic components and introduce a series of molecules with the idea of using it to treat lung diseases. We have chosen this bacterium because it already lives in the lung and therefore would not be rejected and could remain active for some time. The idea is to use it to treat intubated patients who have developed hospital pneumonia. This is a very serious problem. Thirteen per cent of affected patients die because they do not respond to antibiotics. The idea is to get this bacterium, once modified and reintroduced into the lung, to dissolve the biofilms and kill the other antibiotic-resistant bacteria. It could also be used as a vaccine in lung cancer, modifying it so that it can block the mechanisms that the tumour uses to evade the immune system.

We’re working on that. We are talking to investors now.

Here are several aspects to take into consideration. One is that scientists have to undertake quality research, work driven by curiosity but always keeping in mind that what we do may bear an impact on society and become something of value. Another is to get public centres to have powerful technology transfer offices. We must also ensure that venture capital, which is now growing in Spain, really takes risks. And above all, the regulatory framework must be changed. The Science Act must be developed, at state and autonomous community level, so that we can get rid of a series of administrative regulations that are hindering research.

Needless to say, we cannot have a state agency and not have a multi-annual budget. I have already given up on reaching 2% of GDP to allocate to investment in science. I would be content if the budget of the National Plan for Basic Research were doubled, which is approximately 400 million euros, the equivalent of three kilometres of the AVE [high-speed train]. All parties concur; I do not understand why it isn’t being done.

We compete in much worse conditions, there’s no doubt about that. The time spent solving these problems reduces your productivity. And then there’s the uncertainty. When you hire someone you know is good, you don’t know if you’ll have the money to keep them on. You have to give them a permanent job, but then if you don’t have the funds, you have to fire them. Project contracts must be put in place. This arrangement is already featured in the decree, but it is not well developed and cannot be applied.

Well, all those moments of uncertainty and tension affect you, especially in an internationally-renowned centre like ours. The conflict was broadcast on televisions all over the world. We have about 30 group leaders and some 500 people staffing the teams. People were asking questions, they were concerned. It doesn’t seem to affect them much anymore now. And when it comes to attracting talent, we were able to hire excellent group leaders who could opt for other destinations.

That’s true, but university needs a change. As required by the CSIC [Spanish National Research Council], which should have a similar structure to the Max Planck institutes in Germany, with a central body that ensures quality and autonomy in management for the centres. Being competitive is harder for a university than for a centre like ours, not because they don’t have good researchers, but because they are more restricted. You have to cut through the red tape. It’s a shame to see young people who have come from elsewhere with a Ramón y Cajal place who throw in the towel after two years because they get tired of fighting windmills.

We also have the capacity to attract talent here. Sixty per cent of CRG staff and 65% of group leaders are foreigners. But we also have good people from here. I am proud that two of our youngest group leaders did their thesis here; they subsequently went abroad and have returned to compete with scientists from Harvard, EMBL Heidelberg and the Francis Crick Institute. A crowd of people who trained here and are now internationally competitive are returning. And we have at least seven or eight post-docs who are group leaders in Europe. We should remind ourselves that what we have done is staggering, but let’s improve on it. When I joined the CRG, I recall having an argument with Miguel Beato, its first director, about what we wanted to be. The very obvious conclusion was that we wanted to compete in the world league. Barcelona must aspire to be the Boston of Europe. And for that you have to take a gamble that does not require billions, but rather smart reforms.