By Maria Guimarães – Research Fapesp Magazine – Issue 276 – feb. 2019 (Photo by Léo Ramos Chaves)
Self-declared molecular tamer, physicist ally scientific research to administrative management
Glaucius Oliva’s passion for taming proteins for drug development was born in undergraduate, an engineering challenge: figuring out how to attach dozens of plastic pecks in the form of a myoglobin molecule. It was months of work to calculate the exact position and orientation of each atom and position them all, sticking the parts and fitting them into wires cut to the precise length. From there, the electrical engineering student knew what he wanted to do.
He just did not know that this scientific interest would also require him to devote himself from the beginning of his career to bringing together specialists in different fields to work together and to persuade development agencies and research institutions to finance them. Glaucius Oliva then became a leading manager, both in major interdisciplinary projects and ahead of the National Council for Scientific and Technological Development (CNPq), which presided between 2011 and 2015. Professor at the Institute of Physics of the campus of São Carlos of the University of São Paulo (USP), currently directs the Center for Research and Innovation in Biodiversity and Drug Discovery (CIBFar), one of the Research, Innovation and Dissemination Centers (Cepid) funded by FAPESP.
Oliva granted this interview in his room decorated by the molecular model assembled about 40 years ago, in a practically empty institute on the eve of Christmas. His lab was active.
His work has made him stand out in both management and research. What is your main facet?
These two things are tangled in my story. I never stopped doing research. Even during administrative management positions I was in the laboratory, because I find it very bad when the researcher becomes manager and forgets his life. In general the disconnection with his activity-end the distance of the difficulties, the problems, the challenges. Management in science and technology means making daily choices of how to use resources to achieve goals.
They are also involved in coordinating a research center.
Yes. I have always coordinated large projects, starting with the first round of thematic projects funded by FAPESP shortly after I finished my doctorate in 1988 and returned from England. We were able to equip the lab thanks to this. Then came other networking projects, because our area is very interdisciplinary. We’re at the Institute of Physics, but we need biology, computation, chemistry. In the beginning collaboration with groups that produced the proteins to study was fundamental.
Does Cepid take a lot of management effort?
We are 22 principal researchers, in addition to the students, and we have administrative support. One of the challenges of coordinating such a project is to integrate researchers. Since they are all good and independent, you have to convince them that it is worth collaborating with each other. If each one continues to do only their tasks, we will have a good list of publications for the report. But CIBFar’s focus is a drug, and Brazil has no history of innovation in this area. It needs to have the biologist, the structural biologist – who studies the structure of the molecules – and the chemist. And someone who is looking at the whole, the coordinator. I do not go in the lab any more to tinker with test tubes, but I go in every day.
There was no place where a promising substance could be studied in an integrated way
From research to production, what is missing?
The national pharmaceutical industry is very well garnished in the formulation part, production. With the legislation that regulated the generics, it was necessary to learn to make drugs with qualification. Now the challenge is to innovate. Imagine that the drug needs to find a receptor to fit in a way that produces a certain effect, which is to activate or deactivate some protein. Finding a molecule is not easy, we have in our body thousands of proteins, with thousands of different structures. Side effects usually happen when the molecules of a drug stick to things they find along the way. To tame a molecule that runs through the body to the target is an art that still involves trial and error, with synthesis of different molecules.
And does each illness work in a way?
With microorganisms it is necessary to determine the essential protein to its survival, in order to have a validated target. Many people study the disease-causing microorganisms, how they produce symptoms, attach themselves to the cell they want to invade, inject genetic material or proteins into it. I have always worked with Chagas disease, schistosomiasis, leishmaniasis, but other colleagues took care of it when I was in CNPq between 2011 and 2015. When I came back, it was the moment when the zika epidemic happened. So we started a project on arboviruses, today we work with zika, yellow fever and chikungunya. A few decades ago the process was very experimental and was by chance. It changed when we understood the biology of diseases better and began to study the structure of the proteins that interact with them.
It takes a crowd to cover the chain of knowledge. Missing people?
Missing thread. We have a researcher who understands pharmacokinetics in rats, another who does toxicology, others who study the fundamental biology of diseases, who work with protein structure or chemical synthesis. But it takes an orchestra. If everyone cares only about their sound, they have never seen a symphony. Brazilian science is still extremely disciplined. In universities, departments are separate. The undergraduate courses are watertight, there is no chance of picking up a student who understands physics to use X-ray and biophysical fluorescence techniques, and at the same time knows what a bacterium is like the molecular biology of cloning a gene.
Is CIBFar an evolution of the former?
We present the first proposal in 1998, on the first call of Cepid. The program was born because we told José Fernando Perez, then scientific director of FAPESP, that modern science is multidisciplinary. I realized this because in 1996 we were working with Chagas disease, a thematic that allowed us to construct a light line in the LNLS [National Synchrotron Light Laboratory] to analyze the structure of proteins. For this it is necessary to have crystals, where the atoms are ordered. But in a crystal of 1 tenth of a millimeter are 1013 molecules of protein: 1 followed by 13 zeros, several trillions of molecules that need to be ordered, does work. Then I met at a congress an American biochemist at the University of Alabama at Birmingham, Lawrence DeLucas, who was an astronaut and worked for NASA on a microgravity protein crystallization project. In this condition it is possible to obtain crystals more easily, and he invited me to do an experiment on the International Space Station. It was the first space-based Brazilian experiment launched on the Columbia space shuttle in 1997. On the way back from the launch I went to the lab in Birmingham, a National Science Foundation (NSF) center. They had research centers with this multidisciplinary role and my colleague was at the head of one of them, with biologists, chemists, computer personnel, crystallography and pharmaceuticals, working in an integrated and interacting way with companies. I suggested we have something similar and Professor Perez made a trip to the United States to visit NSF centers. When he returned, he launched the call. Our challenge in the project we presented was to create a critical mass in the structure of biological materials. No one produced pure protein in the country. We had 15 molecular biologists and biologists, and two chemists. Nowadays the challenge of the drug is chemistry and in the current center we inverted the equation: we have 15 chemists and two or three structural biologists.
And the “biodiversity”, in the name of CIBFar, enters where?
It enters as a source of inspiration for active molecules. The drug can not be very polar, because if it is not it crosses no membrane; it can not be very hydrophobic, otherwise it is not soluble; it can not be very labile or it may break; at the same time it can not be very large, but stick to other things. A plant does not run, it does not scream, it stands still. The only defense it have for fungi, insects, phytopathogenic bacteria is chemistry. The biosynthetic routes that make these molecules were selected over billions of years of evolution have been domesticated to interact with other living organisms. From them, you can make modifications to optimize your action and simplify chemistry. Then we can test properties in vitro without the need of animals. There was no place where one could study a promising substance in such an integrated way. This is what CIBFar does.
Do you have results that stand out?
Recently we found a set of molecules to combat malaria, in a project coordinated by my colleague Rafael Guido. The patent is still in preparation. They are extremely potent molecules with promising pharmacokinetic properties that kill the parasite in vitro and in vivo in experiments with mice. They aroused the interest of GlaxoSmithKline, an international pharmaceutical company that contacted us through FAPESP. The molecules were transferred to the development center of Glaxo in Tres Cantos, Spain, through an agreement, and at the moment they undergo tests that are not done in Brazil. Another example discovered by members of Cepid at the Federal University of São Carlos is a natural 10-gingerol molecule, extracted from ginger, which proved effective in preventing metastasis in breast cancer. We have new molecules against yellow fever, for example, with a very large power not yet described in the literature. These are promising results. In the first six years of Cepid we brought people from different areas to work together. Now the structure is assembled and it is time to deliver the results.
You use synchrotron light to elucidate the protein structure. Now a new generation of particle accelerators comes in with Sirius. What changes?
It changes a lot. In my doctorate in 1987, I took a weekend to collect a set of X-ray diffraction data for a protein and six months to process and analyze the 600 photographic plates. Today we ship tanks of liquid nitrogen with protein crystals to the Diamond accelerator in England. Each data collection takes about 30 seconds. Sirius will increase the resolution of X-ray diffraction, will change the terrain using much smaller crystals and generate much faster analyzes than the alternatives we have here and in the world.
You graduated in engineering. Did you imagine another career path?
It was a fluke. I chose electrical engineering, but at the end of the first year a professor who gave me a physics class invited me to help build a vacuum system for some experiments on vacation. Professor Sérgio Mascarenhas was the leader of the biophysical laboratory, always inspiring, motivating. I listened to his introduction to the history of physics and loved it. In the second half of 1978, he had returned from England and showed me a box with which he did not know what to do. It was a set of pieces representing atoms of a molecule of myoglobin, but he had lost the instructions and asked me if I wanted to assemble the model. It took me six months and realized it was what I wanted to do.
How did you become physicist?
In the second year of engineering, I decided to do another entrance exam. In those times it was possible to take two courses at the same time. Both were diurnal, but I adapted. He was already overworked in the chemistry laboratory Yvonne Mascarenhas and the physicist Eduardo Castellano, an Argentine who fled the repression in his country, which made X-ray diffraction in small molecules. No one made a protein structure in the country. When I finished engineering, a free professor of physics – Aldo Craievich – transferred to the Brazilian Center for Physical Research in Rio de Janeiro. At that time, 1981, there was no public tender for teacher admission and the departmental council decided to hire four professors to replace Craievich as teaching assistants: Vanderlei Bagnato, who coordinates another Cepid and is the director of the Institute of Physics; José Nelson Onuchic, now a member of the National Academy of Sciences of the United States; Carlos Antonio Ruggiero; and I. Carlos Antonio and I still did not have a degree. The others had graduated the year before and were hired immediately. Therefore, my contract with USP as a teacher has the date of December 18, 1981, the day I graduated.
Mudamos a graduação no instituto para tirar o aluno da sala de aula e botá-lo para trabalhar
Did you finish your physics course?
At the beginning of 1982 I went to register and I was told that I could not be a student teaching the same institute. So I enrolled in the master’s degree, I made structure of small molecules. It was preparation to be able to make protein structure, which was what I wanted to do forever, and I went to doctoral studies at the University of London, England, with Tom Blundell, an international leader in protein structure. For four years I studied three proteins: a small peptide, a medium peptide, and a very large protein associated with neurodegenerative diseases, such as Alzheimer’s and amyloidoses. It took me six months to collect and process data. To solve the structure were two more years, I surrendered an article in 1994 in the Nature.
Back in Brazil, how did you continue?
There was no structure that would mix protein preparation, crystallization, and X-ray laboratories. When I arrived, director Oscar Hipólito said he had a laboratory for me. It was a room with a sink covered in white tiles. In general physics laboratory has no sink, but he thought that it needed water to work with protein structure. It does not need water to fiddle with laser, it even gets in the way. It was a challenge, we started chasing proteins in people’s labs. Everything was very handmade and did not have adequate material to work with. You had to be creative.
How was the election for rector in which was the most voted, but not named?
In 2006 I was elected director of the institute. Talking with Reina Suely Vilella [2005-2009] I saw that she was solving problems of daily life – money, bidding, student bundle – but we had fundamental problems to think about: where USP was going, how could we rethink graduation … There was not an instance to think about USP in the medium and long term. Then I discovered that in the USP statute of 1988, a planning committee was planned. I spoke to the dean and at the end of 2007 she appointed this committee, which I chaired. We held meetings that lasted all day every month, more or less. We went to some Institute – Piracicaba, São Carlos, São Paulo – and we had the day to discuss central themes. We brought people from abroad to talk about departmental structure and undergraduate course, whether the university needed to be research or teaching, if they all needed to have the same model. He even produced a book, called USP 2034 – Planning the Future. This year, when it came to election rectorship, we realized that it had to materialize into a university for the future and the idea of having a candidate for rector was born. In the first months of 2009, we translated it into a management project. In June I became a candidate, the university community liked having a project built by so many people. I was the most voted in the first and second round. But the then governor José Serra chose Grandino Rodas.
Then came the CNPq.
I was the director of the Institute of Physics, I still had six months in office, but I was uncomfortable. The director has a seat in the University Council … It would be bad for me and for Rodas as rector. In 2010 a physical colleague from Rio, Carlos Aragão, was appointed president of CNPq and invited me to be director. At the end of that year the Aragon left, coincidentally with the change of government. Dilma Rousseff became president, Aloizio Mercadante minister, and he eventually appointed me president of the institution.
After contemplating the first call of the National Institutes of Science and Technology, INCTs, you saw the program on the other side. How do you see it?
We had 120 INCTs funded since 2008, it was foreseen in the announcement that there should be an evaluation. In 2010, and then in 2013, we held three-day events where the coordinators of all INCTs, sometimes one or two people, went to Brasilia. Each of them had a stand where they had to visually show what they were doing. We brought people from the city, from the government, from the congress to see what was being produced. There was an international committee, about 20 people. We organized a symposium divided into themes, each INCT had one hour of presentation and arguing, and everyone else in the same area was watching. It was great, the INCTs knew each other, outside people saw what they were doing. The cost-benefit was very good.
Did it allow you to think more broadly?
Yes, but one of the things I enjoyed doing the most was thematic calls. I wanted to transform the CNPq of a development agency of the Ministry of Science and Technology into a Brazilian state development agency. The directors who worked with me had to go to the ministries to find problems to be solved. We put in a little bit of money, they packed a lot and we launched calls with applied themes. For example, constructive technologies for “Minha casa, minha vida”, technologies suitable for small farms, health – like the problem of dengue. Ministries made money. I made calls with Petrobras for oil and gas projects with Vale. The companies invested.
The role was to organize?
Not only that, CNPq has the tools and can grant scholarships, for example. The scientific community is ready to meet the needs of the country. We are called alienated living within the walls of the university, concerned with the navel itself, with the paper to be published. It’s not like this. If you ask, the scientist contributes to society. If it is not called, it focuses on what the funding agencies require.
How did Science Without Borders come about?
When I arrived at CNPq, I only had 500 overseas grants a year to offer. How are we going to live with a provincial science like this? That year Obama came to visit Brazil and mentioned to Dilma that he had launched the 100,000 Initiative program in the United States, in which he encouraged American universities to send 100,000 students to the world. This is called diplomacy of science: when you send a student abroad and he lives with that community, you create a network of highly qualified people that later ends up generating values far beyond educational. President Dilma decided to do as well and we proposed that the dominant would be postgraduate scholarships, but the demand was very low. Our students were in an exaggerated comfort zone. If you entered the doctorate, you will leave with the title. I had a scholarship, a job in Brazil. There was no stimulus to leave.
The graduation staff thought it was great.
Yes. The great villain of the structure of Brazilian science is the undergraduate, with this compartmentalized system in which the disciplines do not speak to each other, the courses do not either. The undergraduate courses are absolutely aulísticos. It is typical for an engineering student to have 35 or 40 credits in one semester.
Do not have time to be creative?
He sits up watching the professor, who writes on the board. When you say you’ve modernized your class, you’ve switched transparency through PowerPoint. I said that we needed to modernize the Brazilian graduation. No overseas course has more than 15 or 16 hours of class per week. The student goes to the library because he has to deliver reports, take oral exams, the collection is high. Here, the exchange rate of the university professor is to give class. The more disciplines, the more teachers you can hire. In the end has a bloated didactic charge, people without involvement with creativity, innovation. The student is passive the entire graduation and is required that the first day after graduating he will get a job and go be innovative in a company. We do not have innovation in Brazilian companies because the students were not trained to be innovative. By sending them out, they could begin to revolutionize these courses by telling what they learned out there. It was an expensive program, I have no doubts. But we took 100,000 students abroad.
What of that experience did you bring back to university?
I worked with other colleagues to change the undergraduate course in physics. We have three undergraduate courses at the institute: traditional physics, computational physics and biomolecular physical sciences. They were quite isolated from each other, so we unified the first year, we reduced the compulsory didactic load to 50% of what the required load is. The other 50% students can build with optional activities from any of these courses, but also from other campus units. The work of completing the scientific initiation counts as credit in the undergraduate, our goal is to take the student from within the classroom and put it to work. We are in the second year of graduation. Now I am in a new stage of my life, I presented my request for retirement. It does not change anything: I continue as a full professor, with this laboratory and research project, with my graduate students, giving graduation classes. The only thing I can not do is attend council and congregation meetings.
Nor be rector.
So many people call me every time it have a rectoral election asking me if I’m going to be a candidate. Honestly, I want to stay close to my two grandchildren, one with 1 year and one with 5 years.
Original text: http://revistapesquisa.fapesp.br/2019/02/11/glaucius-oliva-estruturas-complexas/