At this moment is taking place at the Palau de la Generalitat in Barcelona the award ceremony for the 2019 Catalonian National Research Awards. Among the awardees is Sílvia Osuna in the category for Young Talent. Below we reproduce (with permission) the translation of an interview that Xavi Aguilar held with Sílvia, and which was published last week in El Punt Avui (in Catalan).
Our problems will end up being solved by scientific research
XAVI AGUILAR – BARCELONA (El Punt Avui, Ciència, October 7, 2020)
Sílvia Osuna, Catalonian National Research Award for Young Talent
Sílvia Osuna (Castelló d’Empúries, 1983) is the winner of the Catalonian National Research Award for Young Talent awarded by the Fundació Catalana per a la Recerca i la Innovació (FCRi). With a PhD in chemistry from the University of Girona (UdG), she is currently an ICREA professor at the Institut de Química Computacional i Catàlisi(IQCC) of the UdG. Her research focuses on the design of new enzymes of industrial interest using computational chemistry tools.
We modify the structure of enzymes to take advantage of their capabilities in the manufacturing of new drugs
In case anyone is lost, what do you say you do?
Some concepts may need clarification in order to understand what exactly is the computational design of enzymes. Enzymes are biomolecules, proteins that, for example, we have in our body and that are responsible for accelerating chemical reactions. Thanks to enzymes, all the reactions that take place in our body can be carried out in a time period that is compatible with life. Molecules that accelerate chemical reactions are called catalysts, and enzymes are the best-known catalysts. The idea behind our research is that these efficient catalysts can be used in industry to make different products of interest, and in our case we have focused on drugs.
That doesn’t sound easy to do…
Although, on paper, enzymes are the most efficient catalysts, they are so in the biological conditions of our body. When we put them in a reactor in industry, they no longer work so well. Therefore, our job is to take the natural enzymes and make the necessary changes to their structure so that we can use them industrially.
And you do this with computer simulations.
Yes, because it has the advantage that you don’t have to test all the structural changes in the lab. Instead, we do computational experiments and make changes to determine which mutations we need to make to get the desired outcome. Enzymes are expensive to treat from a computational point of view, because they have many atoms. What we do are simplifications, because doing it on a more accurate level has a very high computational cost. We use molecular dynamics simulations to determine which changes we need to make in the structure; this brings us some results, and based on those we use algorithms to determine which positions need to be changed.
Your aim is not to do so for specific cases, but to establish a kind of system or protocol to do so in a general way.
Correct. It is a slow and precise work, but we are moving forward. A few years ago we were exploring how to develop new tools to make changes to enzymes. These are now fully developed and we are in the process of applying them, and collaborating with experimental groups to validate whether the predictions we have made are accurate or not. I’m happy because we’re starting to have the first results that show that yes we are capable of designing enzymes, although there remains still a lot of work to be done.
Give me an example of a case that worked.
One we are just validating is an enzyme to make L-tryptophan derivatives, which is used for people with sleep problems. There is a natural enzyme that is able to make it, but it requires other enzymes. Our design allows us to make the reaction we are interested in, generating L-tryptophan, without the presence of other enzymes.
Tryptophan is related to sleep problems. If I would begin to do research, I would not have started here …
I don’t look at what interests the industry, I care more strongly about the academic part. Tryptophan derivatives may not have much interest for their medical aspect, but they do have from an academic point of view, because the natural enzyme is a complicated system. However, we are also doing other enzyme designs to synthesize chiral amines, which are found in the structure of 40% of medicine.
Therefore, the pharmaceutical sector must be following your research closely.
I work on the sideline of pharmaceutical’s interest, even though I know they are interested in our research. Academic interest is different from industry. We go along parallel paths and know each other, but we have different viewpoints.
Given that your approach is computational, you probably need to resort to the Barcelona Supercomputing Center to take advantage of its great computing power.
Yes, we ask them for computing hours to do the simulations and computational experiments, but we have also been able to build a supercomputing cluster at the University of Girona thanks to the research funding of the Starting Grant project granted to me by the European Research Council (ERC). Like this we don’t rely as much on MareNostrum to design the enzymes.
These projects funded by Europe are for a limited time only. Will you want to give it continuity?
The project will end in December 2021. Afterwards, the computer cluster will stay here, in Girona, and will be more available for other research projects. For me, it will be the moment to apply for the ERC Consolidator Grant and continue investigating.
This basic line that is your research, is it for life? Or would you like to study other things?
We still have a long way to go because there are many aspects of enzymes that are not yet known, and we are still far from knowing exactly how they work or being able to make accurate enzyme designs. Therefore, years of research are still ahead of us and I would like to follow that path. However, I am also looking forward to new challenges, looking for a different approach to research but focused on the design of computational enzymes.
Why did you focus on the study of enzymes?
I’ve always liked biochemistry. I had to start with either chemistry or biology and I chose for chemistry. I have always been attracted to biological systems and enzymes are very complex molecules that are very interesting for me to study. Chemists with a more theoretical profile may not find them so interesting, because their very sophisticated methods cannot be applied to study them, but I consider myself more computational than theoretical and the subject has always attracted me a lot.
With the exponential increase in technological tools, do you think that computational chemistry will end up being more important than the experimental part?
Computational chemistry has evolved enormously in a short time since it is linked to the development of supercomputers. As a result, the impact of computational chemistry is growing. When I started my thesis, computational chemists were the odd ones, but today the collaboration between computational and experimental is getting stronger every day. And that will continue to grow. I don’t know if computational chemistry will prevail over experimental chemistry, but experimental chemists will probably have less work to do.
And will that affect drug design? What will the medicine of the future look like?
I think so, because the advantage of these computational methods is that they provide knowledge that is essential for improving their production. But it is still early to predict how things will be.
In the long run could these systems help improve or speed up treatments for Covid-19?
Once it is known which medicine works against the disease or which vaccine is effective against the coronavirus, one could try to design an enzyme to make the manufacturing process of this compound faster. Now we are not doing anything in this regard, because the key is to know what is the active ingredient that makes it work. The moment we know what it is, we’ll get to it.
But what would be the time frame involved?
It is impossible to say without knowing what kind of enzyme we are talking about. The advantage of enzymes is that we can make the reaction millions of times faster and it only gives you the desired product, so you don’t need to take purification steps to get it. Therefore, this has an impact on the cost of the final product: if I get it faster and without so many purification processes, it will be cheaper.
Pharmaceutical companies surely keep track of what you are doing, to target you when the research you do begins to have results applicable to the industry …
There are few examples, but more and more drugs are being made through biocatalysis, i.e. using enzymes. Therefore, obviously, the pharmaceutical sector is waiting and is interested in any progress in this direction.
How has Covid interfered with your research?
We confined ourselves at home thinking it would be for a short time but it lasted quite a bit longer than we expected. We have continued to investigate remotely, but it was not that easy. Our advantage was that we didn’t have to go to a lab and could continue to send calculations to the computer from home.
The good news, if any, is that research has gained visibility.
Regarding society, Covid has helped us realize how important research is. Covid has made us see that, in the end, research will be the one thing that will solve the problems we have. It has made us think and has made science one of the priorities that society must have. It is very good that many initiatives have been launched to fund coronavirus research projects. But I do believe that, just as money has been found to fund such urgent research, there should also be money for super-important projects that may not have such a direct application, but that are important in creating a foundation on which to construct a long-term path.
Being a mom, all the time you don’t spend on research has a direct impact on your curriculum. We still need to improve many things
It seems to me that chemistry is a scientific discipline with a strong presence of women.
Maybe so, but there are different areas, and it varies. In computational chemistry the female proportion is very low, unfortunately, so many more women are needed in this field. The problem, however, is that during the undergraduate studies there are many girls, then in the doctorate there are less, in the postdoctoral even less, and then leading research groups, even less.
But this is a structural problem of science, unfortunately. Being a woman and wanting to be a mother greatly affects the career progress. Did you experience the same?
It is true that it influences it very much. Personally, I was probably a mother later than I would have liked to have been. And from the ignorance of not having any children, you think you will be able to continue as before, but then you see that it is difficult to combine doing research with acting as a mother, because I was traveling to many conferences but also wanted to enjoy time with my son. All the time that you’re not doing research on a daily basis has an impact and affects your curriculum. There is still a lot of ground to run and we need to find a way to make a better combination.
Do awards like the National Research put pressure on you?
They are a recognition of the research path and the efforts put in. The world of scientific research is very complicated; therefore, receiving recognition and being valued gives you a lot of energy and drive to move forward. At the same time, it is also a responsibility. But, I was thrilled with this research award after having had my baby, which gives me extra motivation to continue.
Scientist and artist
Although Sílvia Osuna’s scientific career has been recognized by several prestigious awards, she does not respond to a clear and resounding vocation. “I was doubting very much between studying chemistry or fine arts, because I’ve always liked painting.” In fact, it is an art that she still practices and that has also allowed her to be more effective in her work as a scientist. “Art and science have something in common,” she explains. “There are many aspects of research that have a very creative side, not only to think about how to solve problems, but also to make an image that summarizes and helps explain the results of a research. I enjoy this as much as the research process,” she admits.
