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Interview

Ruth e Victor Nussenzweig: A chemistry that worked out

The couple talks about the advances in the search for vaccines against malaria and of the life of a scientist, here and in the United States

MIGUEL BOYAYANWere it not for a sensible colleague at the School of Medicine of the University of São Paulo (USP), Victor Nussenzweig perhaps might not have become a scientist. Ruth, who had emigrated from her native Vienna to Brazil while she was still a girl, dissuaded him for continuing to take in those boring meetings of the Communist Party and encouraged him to follow the career of a researcher. From the flirting that started in the third year of college, over half a century ago, there arose a lifelong partnership. Inside the laboratories and outside. “We would be courting and talking about science”, they recall, both of them 76 years old today. The military coup in 1964 led Ruth and Victor, who in those days already had more than a foot abroad, to transfer themselves definitively to the School of Medicine of New York University (NYU), where they remain to this day – she in the Medical and Molecular Parasitology Department, he in the Pathology Department.

In an interview granted during a recent visit to São Paulo, the couple comments on the latest advances in the researches for developing a vaccine against malaria, an issue  they have been pursuing for decades. Their name is forever linked with the fight against the disease that, every year, kills at least a million persons in Africa and continues to be a threat to several parts of the tropical world, like the Amazon. In 1967, Ruth was the first scientist to prove that it was possible to immunize rodents against the disease, by means of irradiation of the sporozoites, one of the stages in the life of the parasites that cause malaria, of the Plasmodium genus. Later on, in the 1980’s, the Nussenzweig showed that a protein that covers the parasite could be used to promote an immune response against the disease and thereby give some protection against the infection. Since then, the protein studied by the couple has become a fundamental component of half of the vaccines that have been and are being tested on humans against the parasite. Including a formulation recently tested in Africa, with promising results.

The Nussenzweigs also talk about a new line of work, in collaboration with the Oswaldo Cruz Foundation (Fiocruz), of Rio de Janeiro, in which they are going to try to develop a malaria vaccine that uses the one for yellow fever, produced in Brazil, as its vector. They also comment on the life of a researcher in New York, the facilities and the difficulties to get funding in science, and recall the circumstances that made then leave Brazil forever. Forever, to a certain point. They visit the country frequently, for reasons of work or to see friends and relatives. Of their three children, all scientists, two are in the United States and one in the city of São Paulo.

Isn’t it difficult to sell to the Americans the idea that it is necessary to invest in research into a vaccine against malaria, today a disease of poor countries?
Victor – However incredible it may seem, the National Institutes of Health (NIH) are very generous. Of course, the budget for tropical diseases is not the same as for cancer or heart attacks. But there is plenty of money involved with malaria, perhaps more than in Brazil.
Ruth – My view is a little different. It is difficult to get money from various sources. The main source for all research in the United States is the NIH. You get money, but there is a lot of competition for the allocation. The funds for my researches have come above all from two places. One was Usaid (the United States Agency for International Development), which is very political. Usaid has developed an area for malaria vaccine research. They gave money to a few laboratories, some four or five, and ours was the only one that produced something. I received millions for several years. Afterwards, the allocation was discontinued, the policy changed. The second very important source of financing, not simultaneous with the previous one,  appeared later. It was a foundation called the Starr Foundation, whose financing for our researched extended for some nine or ten years. With the money – millions -, we bought new apparatuses, because there was nothing, it was extremely primitive.

In what period did this happen?
V – In the 1980s.
R – I think it was even a bit before, in the mid-70’s. This foundation would give the faculty shares, and when they had finished the shares, it gave a donation. It gave three donations over the nine-year period, which helped to renovate the department physically; it used to occupy a six floor building plus the basement. The basement, a horrible disgusting place that used to be used by the city of New York for giving vaccines, was transformed into a place for keeping the research animals.
V – There are two important points to emphasize in this story of funding. First: American millionaires donate money for research with great frequency. Immense foundations, like the Howard Hughes, are the prop for research in the United States almost as much as the NIH itself. The Bill & Melinda Gates Foundation gives a lot of money for various things. In Brazil, this is very rare.
R – In the United States, the private foundations have many advantages. They pay no tax or pay less tax.
V – The tax advantage, incidentally, is just at the beginning. The millionaire who donates, shall we say, US$ 500 million, deducts this amount only once from the tax. After that, he no longer has any control, or very little, over the money. The millionaire is also obliged to arrange a group of people, sometimes a member of the family, to take care of the foundation.  Many foundations began like that, although some have nothing to do with their origin.

They professionalize themselves almost like an agency that fosters research.
V –
 Precisely. They turn themselves into a development agency with the name of their founder. But the money for parasitology itself, the basic, still comes from the NIH.
R – I would also like to call attention to the fact that the major part of the money from these foundations is earmarked for a certain disease. There is, for example, a foundation that finances only research into arthritis. Today, there is no foundation funding research into malaria. There used to be the Starr.

Doesn’t the foundation exist any more?
R – It exists, but today it finances other kinds of research, and there’s no foundation just for malaria.
V – I would like to tell you an anecdote, for you to see how this business works. When I was working with basic immunology, I was indirectly studying something that has a relationship with lupus erythematosus, a very frequent autoimmune disease.  In those days, there was the  Kroc Foundation, created in the 1960’s by the owner of McDonald’s a Hungarian called Ray Kroc. This Kroc Foundation was very interested in studies about lupus, because a member of the family had the disease. So, I won a scholarship with a duration of one year. At the end of the period, they gave me the following news: this business of funding  lupus is over, we are now financing (research into) alcoholism. The change occurred because another member of the family was an alcoholic. This kind of thing doesn’t happen frequently, but it happens. At the bottom line , this is not important. Alcoholism or lupus, because of members of the family or otherwise, the foundations are always investing money in important social problems.

Why are there no private foundations in Brazil financing research?
V –
 That is a question that I ask as well. The foundations are a business of the Anglo-Saxon culture. I don’t know, I cannot say what the origins of this are. This culture is in fact very deep rooted both in England and in the United States. In France, in Italy, in Brazil, it isn’t. But don’t forget that there are some exceptions. For example, we now have a millionaire from here, called Ricardo Semler, who held a meeting with scientists and thinkers (it was an event of the DNA Brazil Institute that took place in September).
R – I think that, besides this, there has to be a legislation that gives the same advantage to Brazilian millionaires as in the United States. This is very important, at least to begin with.
V – It also depends a lot on local initiative. For example: you have to have access to these millionaires. Who are these millionaires? University rectors have to have the initiative to try to get in touch with the guys who have a lot of money, who are often intelligent, and convince them that the money they are going to give will be useful.  The rich have to be convinced that the money is not going to be thrown away. A lot of people are still skeptical with relation to the quality of science in Brazil. They think that nothing of any importance is going to come out of here, which is not true. In the United States, the universities – I’m talking about the private one, which are many, some of them the best in the country – keep boards with millionaires and famous scientists who take care of all the management. They choose the rector. The millionaires are satisfied because they influence policy at Harvard or NYU. And, at the same time, they establish financial contacts for the university.
R – They also have a personal compensation in the sense that their name is given to a hospital, to a school of the university. The more money a millionaire donates, the more prestige he gains – the bigger the plate with his name at the university.
V – It’s curious. In the United States, a lot of people have a desire for immortality. Here, the ambitious guy has the ambition of becoming the name of a street when he dies. If he is very important, he becomes the name of a tunnel.

What is the assessment you make of Brazilian science nowadays?
R –
 The scientific level is often very high. I’m not saying this is true for the great majority, but for a good deal of Brazilian researchers. Why do I say this? Personal experience. For several years, I took part in an American foundation, the Pew Foundation, which pays generous scholarships for students from all over Latin America to perfect themselves in American laboratories. The Brazilians were often, almost always, I think, the best candidates for the scholarships.
V – In Latin America, I have no doubt: Brazil and Argentina used to provide the whole contingent of these scholarship holders.

Why have the temperate countries practically eliminated malaria and the tropical ones not yet managed to do the same?
V –
 Basic sanitation. Do you know that there is a period in Italy – it seems incredible – in which the pope was dying and the cardinals had to go there. But they didn’t want to go, because they were afraid of dying of malaria. That is extremely well known. They had to postpone the election because there were swamps and mosquitoes. When it was discovered that mosquitoes of the Anopheles genus transmitted malaria, sanitation was the solution. On the coast of the United States, there was also a lot of malaria, and sanitation resolved the problem.
R – That and economic progress.

So, if we had done the same in the Amazon…
V – But in the Amazon you can’t do sanitation. How can you do this in the forest? Remember that malaria is also transmitted in the forest. The guy leaves home to work and is stung by a mosquito. It’s not like Chagas’s disease, where you can spray the shacks of the inhabitants and eliminate the kissing bug (which transmits the disease). Brazil could eliminate malaria. In the coastal areas, it’s easy. But in the Amazon, it’s complicated. Are you going to destroy the forest, cut down the trees? You can’t do that. So it’s difficult to implant sanitation in the whole region.
R – But, Victor, maybe it’s mot possible to eliminate malaria from the whole of the Amazonian region, because there are areas in an immense transmission of the disease, like those illegal excavations of gold and stones, had been treated with insecticides, the situation could be better and restricted to certain focuses.
V – But, Ruth, in Brazil today the public health service is very good in this regard. It is extremely rare for anyone to die of malaria.

Official data, from 2002, point to about a hundred deaths a year. But the incidence of malaria, which was much greater in the past, is still high, something like 350,000 cases, almost all in the Amazon.
R – But the improvement is also due to another reason. There has been a very great change in the kind of malaria present in Brazil. This change happened perhaps ten years back, I don’t know exactly. People who were suffering from serious malaria, caused by the Plasmodium falciparum parasite, and who were more or less near a public health center, would go there and get treated right away. This measure also eliminated part of the parasite that was responsible for the transmission.  With this, transmission by P. falciparum decreased a lot, and there then arose another kind of infection. The infection caused by Plasmodium vivax, which kills very little.

Today, P. vivax accounts for some 80% of the cases in Brazil.
R – As infection by vivax can be treated, mortality has decreased a lot. But vivax as well is a serious case, and it is going to be more serious in the future, because the parasite is becoming resistant to the cheapest drug against malaria, chloroquine. This has already happened in some Asian countries and, sooner or later, it is going to happen here. When this occurs, there will be relapse after relapse. In a tropical region, the vivax causes very frequent relapses, several a year. Then the situation is going to get worse.
V – Now, you have the following: Brazil is rich and there are new drugs, which are much more expensive. But I imagine that, in Brazil, the picture is always less catastrophic than in Africa.
R – Ah, there’s no doubt.
V – In Brazil, health and wealth make it possible for other medicines to be bought. The problem is that they are more expensive and more toxic.

Which medicines, for example?
V –
 I don’t make this medicine, but there’s this Chinese medicine, a herb…

Wormwood?
R –
 Wormwood is fantastic.

Some people advocate its joint use with allopathy. What do you think of that?
R –
 Wormwood has an almost instantaneous effect. It makes the parasitemia drop a lot, but it never eliminates it.  To do away with the parasite, more medication has to be given after the wormwood. But wormwood is very expensive. Nobody in Africa can take it.
V – But it isn’t toxic. It’s a great new medicine. And there are many others. There most important of all this is that, after the genome of the malaria parasite was revealed, there are new targets for therapies.
R – I think it’s going to take another ten years for these new remedies to be tested and adopted in clinical practice.

Why have vaccines against malaria not worked out? At the end of the 1980’s, when candidates for vaccines were developed using your works, did you think it was going to work out?
R – It is going to work out.
V – No, wait a minute. He is asking why there was the initial enthusiasm. It was mainly because of our works. When the tests with humans began, we were extremely enthusiastic. A lot of people thought that that synthetic vaccine that we had the idea for was going to solve the problem. In laboratory animals, the levels of antibodies that were achieved with the vaccine were sufficient for protecting against malaria. But when they did the first test on man, what happened was the following: of the 15 or so volunteers, only three had high titers of antibodies. These three were protected, but it was a very small proportion. Some researchers and the pharmaceutical industry quit the tests when they saw that it wasn’t a cinch, that they had to invest money and human capital. There the work stopped, because there was no more pharmaceutical company interested in leading to a second or third generation of vaccine. It wasn’t just our test that failed. The test of the United States Army, which was also testing a vaccine, got the same result. But as malaria is a very important problem for the American army, research continues to focus on solving this and other questions. They have an excellent research center, the Walter Reed Army Institute of Research.
R – It occupies the whole of a building.
V – And they persisted with the works on this molecule that we discovered for another ten years. They did tests and more tests. In the end, they arrived at a vaccine with this molecule, in a conformation that there’s no point in discussing in detail, with a very powerful adjuvant, which increased its potency. This way, in tests, they managed to protect 70% of the people in the United States who were given the vaccine. But the protection didn’t last long. Even so, they went to Africa where they carried out more tests on the local population.  About 70% of the people became protected with the vaccine, but the effect lasted three months. Afterwards, the quantity of antibodies would fall. The problem is, then, to maintain the protection. A group from the American army and the GlaxoSmithKline laboratory is doing tests in Africa with the same vaccine and new improve it.

Is that the vaccine that recently got promising results in Mozambique?
V – The results of tests of this vaccine in over 2.000 children from 1 to 4 years old were very encouraging. Its efficiency in relation to serious malaria, which can lead to death, was close to 60%. This work came out in an issue of The Lancet magazine in October. And these results were achieved six months after the application of the last dose of vaccine. This really is a triumph. The next step is now under way and is to vaccinate babies. At last, after more than 30 years of work in basic research, a vaccine has come out. And I’m sure that it is still not the end of the story. The vaccine can still be improved. There are today about 30 malaria vaccines under development, at different stages of experimentation. Of these, more or less half are based on the molecule that we discovered. The other half uses other molecules.

Are molecules still the main target for the development of a vaccine?
V – They are in fact the most important, but there are other strategies, including one started by Ruth with collaborators from Fiocruz, in Rio de Janeiro. Previously, the idea was to make the patient produce more antibodies, but it was difficult to arrive at those high levels. But you can also get protection against malaria by attacking the hepatic form of the parasite, which goes from the blood to the liver. To attack the liver, you need cellular immunity. And, to arrive at this cellular immunity, you need another strategy.  Ruth worked more on this. She has an extraordinary and interesting approach: the yellow fever vaccine is used, which contains an weakened virus, like the malaria vector. This is the best vaccine in the world, because you take one dose and the protection is practically for your whole life. The World Health Organization (WHO) asks people to revaccinate themselves every ten years, but it is for an excess of zeal.

What is this line of research like?
R – Using techniques from molecular biology, we inserted into the yellow fever virus a very small portion of the malaria parasite, nine or ten amino acids. We still do not know what is the best place of the vaccine for inserting sequences of malaria. And it is also not known how much can be inserted without making the virus inviable.
V – The idea is to make a vaccine against malaria that needs just one dose to protect people. In Africa, you often only manage to give a vaccine once in a lifetime, when the child is born. And the best thing is that the biggest producer of yellow fever vaccine is here in Brazil.  If the strategy works, a vaccine for malaria is going to be made in Brazil. That is extraordinary, because you don’t need pharmaceutical companies.

When you were medical students, in Brazil, did you realize right away that you would be scientists and were going to work together?
V – That was obvious. We would be dating and talking about science. In great measure, that was our courting. We would talk about science and what we could do. Our ideas would be mingled, they would go together and so they stayed.
R – But our lines of research did not always coincide. At NYU I even had a laboratory that was physically a few blocks from Victor, in another building. In my career, I followed a constant line, and Victor often worked with other new subjects.
V – There were moments when our careers diversified. In 1958, we went to do postdoctoral studies in France. Ruth went to the Collège de France, where she worked on biochemistry. I went to the Institut Pasteur to specialize in immunology. Following this choice, our trajectories really did diversify. In 1960, we went back to Brazil. But, after some time, we saw that it would perhaps be better to continue abroad. So we asked for scholarships to go to the United States.

The dictatorship hadn’t yet begun. Why did you do that?
V – There were always minor problems. Nothing very serious. But we saw that, in Brazil, there was no way we could do what we wanted to quickly. We wanted to learn more, to advance more. So I asked for, and got, a scholarship from the Guggenheim (the John Simon Guggenheim Memorial Foundation, of New York) and went to NYU. With the scholarship, Ruth would naturally have to live with me in the United States.  This time, we decided that she would not go to another research institution. To start with, she would go to work with Baruj Benacerraf (who afterwards was to win the Nobel Prize in Medicine in 1980). But, when we arrived there, Ruth went to work with a researcher called Zoltan Ovary. No, it isn’t a joke. His name really does mean ovary. Ovary, by the way, is a very good guy. In the end, I ended up working directly with Benacerraf. But after two years in the United States, we wanted to go back to Brazil. So, in April 1964, we decided to go back. We arrived at the airport…

Precisely in April!
V – Perhaps it was May or June. Our colleagues from Brazil were already saying “don’t come, there are a lot of problems here”. But come we did.

So the coup had already happened?
V – The coup has already happened, but we didn’t know its intensity. Ruth and I found it odd when we disembarked at the airport and there was no one waiting for us.
R – No, no, no, wait a bit. There were some friends of ours and they said “don’t go to the college”.
V – Ruth’s memory is different from mine. But that’s of no importance. My recollection is that there was no one there. We found it odd, because we had many good friends. But I think that Ruth is right. Actually, they called me later and said “look, don’t go to the school of medicine”. It was Sunday morning and I though it would be good to go to the school. If the situation was difficult, it would perhaps be as well to have a look in my desk, to see if I had some incriminating document, left wing, who knows, of the Communist Party.  And I went there, at 10 o’clock in the morning. I left there at 11, and there was nothing. When I got back home, they telephoned.
R – No, mister, they telephoned me as soon as you left. I picked up the telephone and they said there was already an interview scheduled with you on Monday, the following day, with the secretary-general of the school of medicine.
V – Imagine the situation. On Sunday, I had hardly gone into the school and they already knew I was there. Immediately, someone called home and said that I had an interview with a colonel. I, on my own, without Ruth went to talk to the colonel, who put some weird questions to me, without any sense. Before going to France, we had organized a series of seminars, on biochemistry, on parasitology, which were done for scientists. Well then, they asked me if those meetings were subversive, because they were held behind closed doors. I replied that we were discussing strictly science, no, there was nothing like that. Then I realized that it was really this colonel who giving the orders in the school. If he was giving the orders in the college, he would give them to me. I realized that I would have no power at all. The colonel didn’t care whether I was a professor or not. I realized that I could no longer stay in Brazil. Ruth and I went back to the United States and our careers separated. She went to work with Ovary, and I, with Benacerraf. At this moment there was a coincidence. They needed an immunologist for the chair of parasitology. And, as she had done a brilliant career with Ovary, he strongly recommended her for the job. So she ended up in parasitology. At that point, our careers diverged completely. She stayed in parasitology and after a few years became the chairman, and I carried on in pathology, doing a supplement, working with basic immunology. She soon began to work on malaria.
R – The biology of malaria was already being studied by two professors from the department, but there were no studies with immunology. That’s why they wanted me to go there. I was an assistant, I quickly became a professor – because in the interim the head of the department retired – and they chose me as head. Later on, they created a chair that didn’t exist before, of parasitic diseases. Incidentally, to this date, inn no other faculty of medicine of the United States is there this chair.
V – There is one important thing in this story. As soon as she arrived – and that is why Ruth quickly became the leader of the division – she made a great discovery, that irradiated sporozoites could protect against malaria. A lot of things happened because of this discovery. In the United States, promotions depend a lot on your curriculum, on what you do. It’s a very competitive system, different from the Brazilian one. When a researcher begins to do more important things, he is sought out by other faculties. They wanted us, for example, to go to La Jolla (in the University of California at San Diego). They went so far as to offer her a chair.
R – Later on, Benacerraf himself, after having won the Nobel Prize, offered a very prestigious position for Victor and for me at the Harvard Medical School (to which Benacerraf had transferred himself in 1970). He offered a division, a big deal. Photos of my laboratory were taken to make one just like it at Harvard.

Did this happen in the 1980’s?
V – Yes. On that occasion, we had a lot of support for developing the vaccine. I had already made headway in identifying molecules. Benacerraf thought he ought to take us to Harvard. He did several comings and goings, but it was complicated to get a chair for us.
R – At that time, we were not so young, and they like having a chairman 40 years old.
V – The offer of Harvard created a dilemma. We had students and everything at NYU and we liked New York. Boston (where Harvard is) is a sort of province. Besides that, we had children in New York. For these and other reasons we decided not to accept the invitation, and we stayed at NYU.

Foreigners, with a left wing background, did you have any difficulty in adapting to the United States?
R – It varied a lot for the two of us. I never adapted. I didn’t want to adapt. I didn’t even make an effort and?

Up until today you haven?t adapted?
R – Up until today. And I wasn’t born in Brazil. I came to Brazil when I was already 11 or 12 years old.
V – Ruth is happy and feels well here. It’s basically that. Sometimes, you don’t want to, but you end up adapting. She has adapted, but she likes Brazil. She likes coming here more than being there.
R – My friends are from here. There, I have practically nobody.
V – I adapted perfectly well, I continue to be adapted, and I feel very well in the United States. Not that I don’t feel well in Brazil, I feel very well here as well. But when I arrive here, I feel I have to go back as quickly as possible to do the things that I’m doing. I like what I’m doing.
R – I want to carry on working as well. But I like the United States solely for the facility of doing research in a quick and efficient fashion.

Did you never think of returning to Brazil?
V – There were periods when I would still consider this, but not any more today. After a certain time, you lose this possibility. I’m going to tell you: I tried to come back a littler while ago, some five years ago. I wanted to make an international malaria study center in São Paulo. I contacted several people, I spoke to the rector of the São Paulo School of Medicine, I spoke to a lot of people, even in FAPESP, to see if there was a possibility of arranging positions for this center. But there the thing snarled up. I even wrote a project and sent it to FAPESP, which was willing to support it. But those positions were missing…
R – The center needed to be under a university.
V – In Brazil, they’re not used to working on a thing that guarantees a lifelong career. In the United States, it’s not like that. You get a good salary and a guarantee of three, four, five years of work, and then you go…

You go off to battle.
V – Here the guy already wants to go into a federal or state position, to guarantee his career. So I saw that coming back was impossible.

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