“Barcelona fulfils all the conditions to be the equivalent of Boston in Europe”

Luis Serrano

Retrat de Fina Birulés © Camilla de Maffei

Few scientists can claim to have published three articles in the same issue of Science Magazine. The biochemist Luis Serrano is one of them. Specialising in synthetic and systems biology, he is working on a project to turn a bacterium that nests in the lung into a living drug capable of fighting antibiotic-resistant infections and destroying malignant cells.
Having witnessed and played a leading role in the great strides achieved in biology in recent decades, Serrano does not play God, but he does not stop wondering about the consequences of the revolution scientists have at hand. A revolution that, just as it has completely changed the rules of reproduction, will afford humans the ability to create not only new organisms and life forms, but also to control evolution itself as a species.

Luis Serrano (Madrid, 1959) has directed Barcelona’s Centre for Genomic Regulation (CRG) since 2011. He currently chairs the Somma alliance, which brings together 25 Severo Ochoa Centres and 23 María Maeztu Units of Excellence, making it Spain’s main science platform. Serrano is well-versed with the challenges science must face because he combines his work as a researcher with a management position. He received a PhD in Biochemistry from the Autonomous University of Madrid in 1985, followed by a post-doctorate from the Severo Ochoa Molecular Biology Centre and another from the University of Cambridge. He joined the European Molecular Biology Laboratory in Heidelberg in 1992, where he was group leader and head of the Structural and Computational Biology programme. In 2005, he joined the CRG, a new specialised research body with a vocation for excellence, which had just been set up with the emblematic Miguel Beato at the helm. Employing more than 500 staff in its laboratories, the CRG – located in the Barcelona Biomedical Research Park – is one of the city’s scientific bastions.

In recent decades we have witnessed a revolutionary leap forward in the knowledge of biology. When the human genome was sequenced in 2005, it seemed that it would be very easy to repair defective genes, but that was not the case. Why?

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.

In the case of gene therapy, the first trials began in 1999 in bubble children, but they had to be suspended because two of them died of leukaemia. A moratorium was imposed in 2003 that has lasted until recently. Can gene therapy finally take off now?

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.

For example?

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.

What are the stumbling blocks still facing gene therapy?

The challenge is still to ensure that treatment to correct a mutation takes place in the exact location of the genome, such that there are no unwanted effects, and that it covers as many cells as possible, although we know that, in some cases, modifying 20% is sufficient. In the case of the immune system, this is easy, because blood cells can be extracted. But if you wish to treat the liver, the pancreas or the brain, it is much more complicated.

When the CRISPR gene editing technique was introduced in 2013, which allows gene sequences to be cut, added or altered, it seemed that this issue had finally been solved.

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.

Now there is consensus that only somatic cells, which are already developed, but not germ cells should be treated. How long will this restriction last?

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.

This has already happened. Chinese geneticist He Jiankui claims to have altered the DNA of two embryos. He did so secretly and made the announcement after the girls were born. Their parents were carriers of the AIDS virus and what he did was modify a gene that regulates the mechanism that the virus uses as a gateway to colonise the immune system. It is assumed that neither these girls, nor their offspring, will be able to be infected by the virus.

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.

Thus far, all authorised trials have been justified for medical reasons and always to the patient’s benefit. But couldn’t it also be used to improve certain capabilities?

Retrat de Luis Serrano © Arianna Giménez © Arianna Giménez

Of course. Just as we can correct to cure, we can modify to improve. But this is highly problematic. And it’s not as far off as it seems. We know a mutation that increases muscle mass. Applied to mice, it has given rise to a species known as Schwarzenegger mice, with impressive musculature. There could be parents who might want it in their children to make them champions. We are also aware that, thanks to another mutation, there are people who need very little sleep, less than six hours. But all these mutations have their downside; otherwise, by natural selection we would all have them. There are athletes who produce more red blood cells than normal. They do not need to train at an altitude of 4,000 metres because they already have a mutation that gives them greater stamina, but they are also more likely to form blood clots.

In other words, you have to be very sure before touching anything...

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?

So far the precautionary principle has prevailed. For a long time, sex selection has been carried out through preimplantation genetic diagnosis to avoid sex-linked hereditary diseases, such as haemophilia. But it is not used to satisfy parents’ preference for a particular sex.

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.

Can you choose blue eyes for your child?

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.

In his book, The Case against Perfection, the philosopher Michael Sandel raises the effects that choosing the characteristics of offspring on demand would have. If that happened, he claims it would put an end to the unconditional love of parents for their children, regardless of how they turn out. It is one of the strongest mechanisms that nature has created so that our species take care of their offspring. If parents could decide what their children are like, the relationship would change radically and some day, their children may ask them for explanations.

That’s the way it is. These are thrilling topics that we have to consider because now we can make occasional genetic modifications, but in 50 years’ time, or maybe just 30, it is very likely we can begin to make more complex modifications. This would lead us to a world like the one featured in the film Gattaca: the possibility of looking for the best combination of genes from a father and mother to conceive the best possible child. That would result in two types of people, those selected and those born at random, which would engender all kinds of problems. We are not on this road, we mustn’t get alarmed… but we must keep it in mind.

Especially since when a technique implies an objective improvement, it hardly stops being applied. Would the problem of genetic intervention be that it is executed justly?

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.

In September 2017, the U.S. Food and Drug Administration approved the commercial use of a gene therapy technique for leukaemia. The cost was $500,000. The first gene therapy approved in Europe, Glybera, to treat a woman with a rare disease, cost €900,000. Are these fees compatible with personalised medicine?

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.

Very promising research concerning bacteria is being conducted in your laboratory. What does it involve?

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.

Could it also be used in other types of cancer?

This particular bacterium is in the lung, but the procedure could be used to treat other tumours. Bacteria expressing interleukin 10 are already used to reduce inflammation in colon diseases. A former intern of mine has set up a company in Belgium with the pharmaceutical company Johnson & Johnson to use bacteria in the treatment of juvenile acne, and there is a company in Sweden that uses bacteria to treat skin wounds. They are different applications of the same idea: develop a living drug, a smart pill. The drugs we use now are stupid drugs. A drug neither feels nor suffers. But if you use a living being, and control it, it can detect the environment of each organism and adapt to the needs of each patient.

Have you already set up a company to exploit the applications?

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

Because one of the most important issues of publicly-funded research is how to capitalise on the findings. What must be done?

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.

Retrat de Luis Serrano © Arianna Giménez © Arianna Giménez

This is a pending issue yet to be addressed...

It doesn’t mean we don’t have control, but it has to be a control adapted to what we do. I would currently like to study pigs using the technique we are developing, but since it costs more than €50,000, I have to seek funding through public tendering. There is only one place in Spain where I can execute this study, but when there are more, they do not even wish to take part. It is so laborious that many do not even try. We need forms of control that do not get in the way of our work.

Bureaucracy is not the only problem. Many researchers complain about insufficient budgets.

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.

Do you get the feeling that, by being here, you are competing with your hands tied behind your back?

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.

Does all this jeopardise the position that science has attained?

In Catalonia we have reached a very high point and we are still there. We are competitive on a global scale. The good news is that funding has been upheld, but it has been frozen for five or six years, inflation is beginning to rise and equipment is becoming obsolete. Everyone in Europe believes that Catalonia has been an example of worldwide success, and now that we could reap the rewards, we cannot backtrack. The Catalan Science Act must therefore be approved. There is a draft law heading in the right direction, but it must be presented to the Parliament and passed. We research centres are a business for the Government of Catalonia, because we bring in more money than is given to us. I always tell them: if they channelled a bit more money into the system, it would have a multiplier effect. Too bad they don’t do it.

As a scientist, have you suffered on account of the process [referring to the Catalan independence movement]?

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.

How has the crisis affected scientific structures?

Retrat de Luis Serrano © Arianna Giménez © Arianna Giménez

The crisis has destroyed science’s middle class; many opportunities have been lost. Doubling the National Plan budget would help reinstate all these groups, but in this case, besides money, reforms would be needed. A reform of university, for example, that includes the appointment of the dean by an external committee, things that are not very hard to do.

But that affect many consolidated interests...

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.

To what extent can the city of Barcelona help attract talent?

Barcelona is very attractive. That’s why I’m sad to think that we may lose positions. It has become renowned the world over for its research centres and universities. It fulfils all the conditions to be the equivalent of Boston in Europe: a charming city, the necessary intellectual environment, and now also a critical mass of scientists... We fulfil the conditions, but we must fill in the gaps.

The United States is a scientific powerhouse because it has been importing the world’s best talent for more than a century...

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.

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