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Luiz Travassos

Luiz Rodolpho Raja Gabaglia Travassos: The victories of “Doctor Freshman”

Biochemist identified bacteria that cause hospital infections and developed new drugs to fight cancer

Léo RamosA long time ago, back in 1960, his colleagues called him “Doctor Freshman,” because of his rapid progress. When the students of the Medical School at the University of Brazil – which today is the Federal University of Rio de Janeiro, UFRJ – were still trying to get used to the course, Luiz Rodolpho Travassos was already working in the laboratory learning to deal with microorganisms. With his vocation for science and his dedication, he isolated and characterized a bacteria that causes hospital infections, today classified as Acinetobacter, and he published his first paper when he was still a third year undergraduate.

Travassos grew up surrounded by the world of science. His father was Joaquim Travassos da Rosa, a bacteriologist and virologist who worked at the Butantan Institute and at the Oswaldo Cruz Institute (IOC) in Rio de Janeiro. “I grew up surrounded by the best scientists in the country and I had no doubts about what I wanted to do,” said Travassos in his room at the Federal University of São Paulo (Unifesp), surrounded by books and pictures of his children – one a musician and the other an actress. Both spent part of their childhood in New York, while Luiz worked very hard as a researcher at the start of his career, which even today does not does not stop him feeling nostalgia for those times. “Everything I like in life is there in New York: quality symphonies, opera and theater. I think the cold is great.”

Travassos worked in the 1970’s in New York at Columbia University and at the Sloan Kettering Memorial Cancer Center. He was one of the first specialists in experimental oncology in Brazil and made contributions to the study of Chagas’ disease and of paracoccidioidomicosis, one of the principal systemic fungus infections in the country. He also contributed to the creation of the postgraduate system from 1967 to 1971, when he was a Director of the then National Research Council (Conselho Nacional de Pesquisas), which is now the National Council for Scientific and Technological Development (Conselho Nacional de Desenvolvimento Científico e Tecnológico , CPNq), and was one of the people responsible for the organization and structuring of courses in the area of biology and medical sciences. Today, at 74, he is retired and has two children and three grandchildren, but he continues to supervise Unifesp students and to publish papers. Here are the principal parts of the interview.

In your first year as an undergraduate while you were studying medecine in Rio, you had already worked in a university lab. Why so fast?
My situation was not normal. My father, Joaquim Travassos da Rosa, was a respected scientist who had worked for 27 years at the Butantan Institute. From early on, I had this very strong influence. He was from Belém do Pará. I was born in Rio de Janeiro because part of his family had migrated to the state of Rio de Janeiro. After Butantan, my father returned to Rio and then worked at IOC, which he eventually became responsible for. At that time he was part of the scientific community and was practically a supervisor of Paulo de Góes, who was the Director of the Microbiology Institute. Góes took public office examinations for the School of Pharmacy and afterwards for the Medical School. He brought together the two areas by creating the Microbiology Institute. While I was doing my medical course, he was a professor of medicine. I had this door open, so from my first year in medicine I was in the lab.

Was it already clear that this was the path that you wanted to follow?
Yes, very clear. I studied at the medical school, but not for a clinical vocation. My vocation is biomedical-scientific, which more or less follows my father’s line. In the first year, I was at Carlos Solé-Vernin’s lab, which was more of a bacteriology laboratory. There they studied cocci, a class of pathogenic bacteria, and there I learnt the basic bacteriological techniques. After one year in the lab, I became the monitor for the practical part of the second year students. So they started calling me “Doctor Freshman.” This was because they shaved my head and I used a green freshman’s beret. We isolated bacteria from clinical cases, purulent dermatitis, meningitis, and things of that type. In one of these cases, I isolated a bacterium that morphologically appeared to be Neisseria, a genus of the Gram-negative bacteria. I discovered that that bacteria had been described using the name Mima polymorpha, because it mimicked the Neisseria bacterium. Today it is known as Acinetobacter baumannii, which is a bacterium that is highly resistant to antibiotics and is responsible for a lot of hospital infections.

At that time, was it known what infections it caused?
We had identified the bacteria in cases of pyodermatitis [purulent skin infections] and meningitis and we knew of its very strong pathogenic characteristics and its specific metabolism, very oxidative, different from the fermentative type of Gram-negative bacteria. I published my fist paper during my third or fourth year at university on this subject.

Did you publish it on your own, without the head of the laboratory?
I did the work on my own and I wrote the entire paper. Solé-Vernin worked more with Gram-positive pathogenic cocci. That a new bacterium was as a novelty for him and he thought that he should not be a co-author of the paper. I could have published it in an international journal; however, it was published in the Anais de Microbiologia, because Paulo de Góes created an institutional journal in the institute and at that time, it appeared to be a good thing. However, it finished up hindering my career in part, by diverting the subject from international publication. I published about 10 papers on that topic.

Why did you then change labs?
I moved to Amadeu Cury’s lab because he focused more on biochemistry, which was my vocation. In his lab, there was work carried out on the nutrition of microorganisms and methods of microbiologic dosing. Through Cury, I met a person who was a scientific father to me: Seymour H. Hutner from New York. He worked in a private lab founded by Caryl Parker Haskins, who was also a scientist, author and inventor. The Haskins Laboratories were of a very high standard and occupied three floors of a building in central New York. Haskins had the idea to carry out original research on rare microorganisms and related applications, which in the hands of Hutner resulted in microbiological assays of vitamins and anti cancer drugs. Cury knew of their work on the nutrition of microorganisms and worked for a period with Seymour Hutner, when he learnt to make synthetic culture mediums, sometimes with up to 40 substances, carefully evaluated in terms of composition, quantitative and qualitative equilibrium, etc. Afterwards he brought this knowledge to his lab, which is where there were novelties. There was new equipment, a Warburg that we learnt to calibrate with mercury! I learnt a lot there besides microorganism nutrition; I started to test drugs using microorganisms as an analytical instrument.

Which drugs?
For example, ethyl urethane, an anticancer drug from the early 1960s. Ethionine was an interesting case because it is an analog of methionine, which is an amino acid that is a methyl donor. Ethionine, on the contrary, can transfer an ethyl radical to DNA, which will increase the level of DNA mutation. It is a dangerous amino acid, because the “ethylation” of DNA can result in the growth of a tumor. I started to study ethionine. At that time, tumor cells or mammalian cells were not used, it was all microorganisms. Instead of using eukaryotic mammalian cells, we used a series of yeasts for example, because when we administered ethionine, the cell died. Using yeasts, we figured out how the drug worked. Hutner, on the other hand, used algae and other microorganisms such as Ochromonas malhamensis, a protozoan. He always worked with protozoa to infer how that would work with a mammalian cell. It was Hutner that came up with the idea that yeasts could be used for purposes other than mycological interest in the fungus per se.

Where else was there cancer research in Brazil?
Almost nowhere. It was all starting and there were some taboos in the research of that time. One of them was radioactivity. To measure and use radioactivity at that time in biochemistry was considered a highly sophisticated technique, one that was beyond normal capabilities. When radioactivity was mentioned, it was commented, “this is beyond the reach of the researchers.” There was no instrument to measure radioactivity, nothing. Carlos Chagas Filho at the Biophysica Institute ended this taboo. Together with Eduardo Pena Franca, instruments to measure radioactivity were brought in and the technique started to become accessible. With cancer, it was somewhat similar. If a young person opted to work with experimental oncology, they would say that he was a swindler, at the very least.

But even so, you decided to work on cancer.
Yes, cell culture was a thing that was completely beyond thinking and the person that introduced this here was the German researcher Hertha Meyer – who was already in Brazil – and the Italian researcher Rita Levi-Montalcini. Both worked with Chagas Filho at the Biophysics Institute. Rita researched the growth factors of neuronal cells and for this work, she won the Nobel prize for Medicine in 1986. She had spent some time in Rio in 1953. Before the work of these two researchers, it was almost unknown to talk about tissue culture and tumor cells in Brazil. I had the notion that I was doing something that might be important, but it was completely outside any universe that was studying cancer in Brazil. We are talking about 1960, almost 1970.

What was your time at CNPq like?
After graduating, I went to work on my doctorate, under Amadeu Cury, in 1963. He was a friend of a circle of important people in Brazilian science. One of these was Aristides Leão, chairman of the Brazilian Academy of Sciences for several years. There was also the pharmacologist Lauro Solero, and Antonio Moreira Couceiro, who was then the head of CNPq. On Saturdays, they met to chat and drink whisky. I would go to these meetings and talk with them. From this type of contact came the invitation from Couceiro for me to run the sector of biology and medicinal science at CNPq in 1967. It was a fantastic experience.

Did you have to evaluate projects?
Piles of projects, and not only that. I had to create and promote programs, call people, and carry out administrative work for the sectors of biology and medicinal sciences. It was very interesting, because I met other professors, of physics, chemistry, agronomy, mathematics, etc. We met to prepare reports, to see if there was money left over, and who would spend it. I was the youngest of the group, at the age of about 30. I stayed there for six years and that phase coincided with the following: CNPq had to qualify the so-called centers of excellence, places with quality scientific production, and they were putting together their postgraduate courses on the new system stricto sensu [i.e., programs that lead to master’s degrees and doctorates]. Afterwards, of course, the Federal Education Council would evaluate them to see if they should formally approve these postgraduate courses or not. As it was within my area of responsibility to approve the centers of excellence and postgraduate courses were a sine qua non condition for the centre, I would evaluate the courses as well. All this helped to build up postgraduate education in Brazil.

Do the current criteria come from that time?
Yes, from that time. There were people wanting to put together a postgraduate course in this or that area that would ask my opinion on how to organize the courses. Sometimes we came up with good combinations. For example, there was a professor of biochemistry in Pernambuco who covered a number of areas, but we had to strengthen things with another professor from Ceará. We got them to work together to set up the course. When they wanted to create a postgraduate microbiology course at the Paulista Medical School ( now part of Unifesp), before I came here, I obtained all the criteria for the preparation of theses and dissertations of the courses for which I had written the regulations in Rio, and gave it to them to adapt over here.

When did you decide to go to New York?
I spent one year at the lab of Seymour Hutner’s wife in 1971 with a grant from the Guggenheim Foundation. The second year I stayed with CNPq funding. Hutner was married to Margarita Silva-Hutner, from Porto Rico. She had PhD in mycology from Harvard University. As I had worked with thermophilic yeasts, I went to the mycology lab of Columbia University, run by Margarita. It was a traditional lab, where Elizabeth Hazen had discovered important chemotherapic agents such as the nystatin used against fungi. I took one of my topics there – a method for the microbiologic assay of carnitine, an essential transport agent for fatty acids in the heart – and they gave me a lab to continue my work. I was on my own, which was not ideal for me because I was learning nothing new. Kenneth O. Lloyd was working in a lab next to mine; he was from Wales and worked on the biochemistry of fungi. I moved  there, as it was what I wanted to learn about. I spent two and a half years there from 1971 to 1974.

What happened then?
Lloyd had been supervised by Elvin Kabat, an important person in the world of immunochemistry, who together with Baruj Benacerraf, who won the Nobel prize for Medicine in 1980, was the student of Michael Heidelberger, one of the fathers of modern immunology. Lloyd and Kabat worked a lot with the immunochemistry of carbohydrates and polysaccharides. With Lloyd, I learnt the chemistry of carbohydrates and made a contribution, because at that time the study of heteropolysaccharides was delimited from the point of view of basic chemistry. During that time, Lloyd started to collaborate with the Englishman Philip Gorin, who went to Canada and was developing the analysis of polysaccharides using nuclear magnetic resonance. This lead to a great advance in the identification of the structure of carbohydrates and polysaccharides. Through Lloyd, I started to interact with Gorin, which had important consequences because, besides learning the basic chemistry of the polysaccharide structure, when I returned to Brazil, I set up a service of glycobiology [the study of structures and functions of molecules connected to the carbohydrates found in cells] in the Microbiology Institute of UFRJ in 1974. I managed to bring Gorin to UFRJ while I set up the service and he stayed for one year in my lab, researching and trying things out.

Why did you return to New York?
The return to Brazil after my first trip was traumatic. All that I liked in life was in New York: good quality symphonic music, opera, theater. I liked the cultural life and the parks. I think the cold is great. My two children, Marta and Alexandre, got on marvelously well there, they made friends, and my scientific productivity was excellent. I was an associate professor at UFRJ, but the grant finished and I could not support myself over there. I looked for a post but they were always temporary. It was an unstable situation for someone who had a family and guaranteed employment for the rest of their life in Brazil. In 1976, I passed a public examination to become a senior professor at UFRJ. It was traumatic, first, to work at Ilha do Fundão in Rio, where the campus is located. Previously we had been in Praia Vermelha. No one would believe the stories I can tell about Fundão!

Like what, for example?
The wild vegetation was about two meters high. We found a snake in the corridors. There were a lot of rats chewing the electrical cables. It was an inhospitable place, a landfill where a building that looked like a jail had been built. It had a concrete structure, with slabs, and if anyone in the laboratory decided to wash the floor, the water leaked down onto the floor below. At that time, the Maré shantytown was alongside. If the window was open, there was the smell of sewage. The contrast was violent relative to what I had experienced before. So much so that I remained there for only a short time.

Even so, you managed to set up the laboratory?
I did. There were always talented students doing their doctorates and we were able to interact. For example, there was microbiology and next to it, there was the Brazilian Center for Natural Products, where chemistry was studied; next to that was the Biophysical Institute, where Carlos Chagas worked, and nearby the morphology department. It was possible to interact despite that strange structure. We managed to create a good work environment. Although far from ideal. I took the public examination for Department Head in 1976, but I was still thinking about New York. At that point, something interesting happened. Kenneth Lloyd lost his job at Columbia, because another head of the Dermatology department arrived there and he wanted to use a more clinical approach, with radiological applications instead of research. As Lloyd was working on the biochemistry of fungi, he lost his job and went to work at the University of Texas in Lubbock, a town on the edge of a desert. He survived but was unhappy. By a stroke of luck, Lloyd J. Old, from the Sloan Kettering Memorial Cancer Center, one of the largest cancer centers in the world, managed to take Ken Lloyd back to New York. As I continued to collaborate with Lloyd, when he went there I told him “I want to go as well.” In 1978, I went to Sloan Kettering. It was another sensational time in New York.

During this second period, did you work only on cancer?
Yes, only on cancer. We searched for specific antigens for malignant melanoma cells attempt immunotherapy. Lloyd Old, the laboratory head, started to identify and classify these molecules because their nature was unknown. He identified antigens using serological reactions, but only later were the cancer-testis antigens recognized, fetal antigens maintained in non-differentiated cells and individual antigens from the specific patient. I started to work on this and perhaps the peak of the work was when we managed to identify a glycolipid – ganglioside GD3 – as the hyperexpressive antigen in melanoma. This glycolipid was recognized by monoclonal antibody R24, which was patented for the treatment of melanoma, which specifically recognizes this ganglioside. It turned into drug.

How many patents do you have?
At Sloan Kettering there were two patents on the gangliosides GD2 and GD3. You are recognized as the inventor but the patent is the property of the hospital. My work has been cited more than 500 times in  literature and it is about R24 recognizing GD3; this yielded a patent. I also took out a patent in the United States for a Chagas disease diagnosis method and there are two more that have been submitted. On paracoccidioides and peptide 10, I have three patents filed, and one more on an adjuvant, together with the Butantan Foundation.

And your second return to Rio?
It was traumatic again. In 1979-80, they were building the metro in the city. I lived in Flamengo. From José de Alencar square to the largo do Machado it was just a crater. The quality of life there was going to be so bad there that while I was still in New York I was making contacts to move to the Paulista Medical School. To transfer from UFRJ to EPM, which was also federal, was quite an easy thing to achieve and I was well received.

What was the line of research at EPM?
It was not possible to continue working with immunochemistry for the treatment of cancer because here there was almost nothing. There were two themes one could work on at that time: paracoccidioidomycosis, the principle systematic fungus in Brazil, and Chagas’ disease. I chose to work on Chagas’ disease and I made some good progress. One student that worked with me, Igor de Almeida, identified important antibodies that could combat Trypanosoma cruzi. This research has evolved very favorably and may contribute in the future to a vaccine against Chagas. It was a beautiful piece of work and today he is at the University of Texas. It also generated an international patent.

Do you believe a Chagas vaccine is possible?
It is a point for discussion. What would be the function of a vaccine for a person who is already chronically infected? The concept of a cure is always a complicated question, although we believe that we have a diagnostic method of high sensitivity for the active disease. We may manage to develop a vaccine for those who live or travel through the region where the disease is endemic or perhaps a combination with chemotherapeutic agent.

How is the work against Paracoccidioidomycosis doing?
This was another breakthrough. First, because for many years the main Paracoccidioides brasiliensis fungus antigen was unknown. Some years ago, another talented student, Rosana Puccia, isolated and characterized this antigen, which is a glycoprotein named GP43. This was important because no one knew what was the principal P. brasiliensis antigen. Afterwards I had another student, Carlos Taborda, now a professor at the University of Sao Paulo (USP), and I suggested identifying GP43, which was the peptide or epitope of the protein responsible for the immune response of the cell. In his doctoral thesis, he mapped out all the peptides that constituted the entire protein and we arrived at a peptide of 15 amino acids that was responsible for the cell immune reaction mediated by T-CD4 lymphocites. We started a series of studies to see whether animals could be protected by the peptide. We inoculated the peptide with an adjuvant and it initiated an immune reaction against the fungus. In the last work that we published recently in Plos Neglected Tropical Diseases, we did gene therapy with a mini-gene that coded the peptide. Instead of injecting the peptide, DNA is injected, which has to enter the cell and then the cell produces the peptide. This causes less toxicity and reduces the inflammation reaction. We carried out tests on animals with very positive results and there was complete protection after long periods of infection.

What is your work like in the area of experimental oncology today?
It focuses on the action of peptides with anti-tumoral activity. In collaboration with a group from the University of Parma, in Italy, the peptide derivatives of immunoglobulins and other signaling proteins are being studied. Apart from this, following an invitation from José Fernando Perez, I am also working for Recepta Biopharma, which represents a step beyond academic activity, with the possibility of converting the findings of lab research into a practical clinical application.

Let us talk a little about your father Joaquim Travassos Rosa. Did he leave IOC for political reasons?
When he was the director of IOC, the Minister of Health was changed several times. In the middle of his term, he was secretary of state for the parliamentary regime, and he returned to the administration of IOC after the military coup of 1964. However, the last health minister that was appointed, Raymundo de Britto, turned on the pressure, with inquiries and disgraceful questionnaires that attacked several researchers from IOC, accusing them of subversion. While my father was there, he did not allow any type of persecution. In the end, he asked to leave twice and the second time was replaced by Francisco Rocha Lagoa. At that time, they said that Rocha Lagoa had been chosen because he was “a poor scientist, a poor administrator, but a good anticommunist.” There then followed what we know even today as the Manguinhos massacre, which sealed up labs such as that of Walter Oswaldo Cruz, conducted interrogations, and dished out punishments. On the day that Rocha Lagoa took up the post, there were a lot of people who would greet my father and then leave, to avoid greeting the new director. Everything derailed during that time, it was terrible.

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