Love at first (insect) bite

older coupleBiting mosquitoes seldom attack alone. No surprise then, that scientists seeking to eradicate malaria, still one of the world’s most significant risks to human health, also hunt in couples. This blog profiles the father of modern malaria vaccines, Victor Nussenzweig, who I recently spoke with. What’s most inspiring is that, at 84 years of age, this scientist just keeps on going. In fact, after successful projects that  would represent the work of at least one richly-packed lifetime, he’s ready to start out all over again.

Victor Nussenzweig and his wife Ruth had phenomenal 50-year careers at New York University’s Langone Medical Center, one of the world’s top medical research institutes.  Professor Ruth Nussenzweig, the C.V. Starr Professor at New York University, has just as illustrious a name in the field of malaria studies as her husband.

Their pioneering work on the biology of the malaria sporozoites paved the way for a vaccine against the deadly Plasmodium falciparum. The vaccine is named RTS,S and has been developed by the pharmaceutical company GlaxoSmithKline (GSK).

mosquito_1944461c

The active component of RTS,S is the coat protein of sporozoites and is named circumsporozoite protein. It was discovered and characterized by Drs. Nussenzweig.  RTS,S is now in final trials with thousands of African children.  Up to now its efficacy has been between 35-50%. The final results of RTS,S trials in Africa will be reported in early 2014.

Together with other prophylactic measures the vaccine may improve the lives of hundreds of millions and prevent a large number of infant deaths each year.

malaria in Africa

These breakthroughs have taken a new generation anti-malarials far beyond the still-prevalent prophylactics derived from the original treatment with quinine.

Antibodies to the circumsporozaite protein only inhibit the infectivity sporozoites that are injected by mosquitoes. However, some sporozoites may escape and manage to enter hepatocytes. Prof. Victor and Ruth Nussenzweig’s research showed in addition that the liver stages of the parasite can be destroyed by cell-mediated immunity; they showed that T cells secreting interferon gamma prevent the development of the hepatic stages.

malaria in AFrica 2

But the couple aren’t finished yet. Remarkably, the 84 year-old, husband-wife New York-based scientists are now doing the equivalent of starting over in a new continent, with a fresh immunological challenge on an even greater scale.

Since late 2010, Professors. Victor and Ruth Nussenzweig have been making visits to São Paulo, the undisputed center of Brazil’s growing scientific research establishment. There they are setting up a research laboratory at the Escola Paulista de Medicina (EPM), attached to the UNIFESP, the Federal University of the State of São Paulo.

They have joined the group of Dr. Mauricio Rodrigues at the EPM who is determined to generate a vaccine against the less virulent but still debilitating Plasmodium vivax malaria that’s endemic to the Amazon basin and hotter regions of this continent, as well as parts of Asia, Africa and north America.

range of malaria Brasil

Ending the infectious cycle of P.vivax would benefit the lives of an estimated 2.5 billion people.

In the last couple of years, Prof. Victor Nussenzweig and his co-worker Dr. Min Zhang discovered that during its life cycle the malaria parasite undergoes obligatory latent or rest stages. For example, sporozoites can remain dormant for days in the salivary gland of mosquitoes. Importantly, they found that latency is controlled by an enzyme, a kinase. If they can find drugs that inhibit that specific kinase the parasite will be killed. Nussenzweig could be on the verge of a second “life’s work,” by alleviating long-term human suffering for millions of patients affected with malaria.

Plasmodiumfalciparum

So the energetic immunologist plans to keep busy for years to come — yet he’s philosophical too. “I’m still active, yes – but I’m 84 years old and ‘long-term’ has a different meaning for me,” says the scientist. “This work is what I live for, and travelling to and from São Paulo and New York is no hardship.”

Prof. Nussenzweig’s three-year plan for research in Brazil is part of a new program called São Paulo Excellence Chair, funded by the São Paulo Research Institute (FAPESP). This is Brazil’s leading regional R&D finding agency with a budget of some US$500 million.

Prof. Nussenzweig is only the second senior scientist of international reputation to win the award, under which a research leader and team develop their project during regular visits to Brazil, while teaching, training and developing the careers of young Brazilian scientists. Tenured researchers also maintain their own projects ‘back home’ – in the Nussenzweigs’ case at NYU medical Center.

So the award to the malaria expert represents a double bonus for FAPESP and Brazilian science, which is getting two Nussenzweigs, not just one. If one Googles the name, there is almost no reputable scholarly paper on malaria-borne immunology to which Nussenzweig, V. or Nussenzweig, R. have not contributed.

(In fact there is a whole tribe of medical Nussenzweigs, for Ruth and Victor’s three children are all doctors: Michel, MD, PhD, a researcher at the Rockefeller University; Sonia, PhD, an anthropologist working in the School of Preventive Medicine of the University of São Paulo; and Andre, PhD, working at the US National  Cancer Institute, National Institutes of Health. And in Rio de Janeiro, Victor’s brother H. Moyses is a renowned theoretical physicist whose children Helena and Paulo are also well known scientists.

Ruth and Victor Nussenzweig have worked closely together and since the late 1950s they have shared the credit both for scientific breakthroughs and for training a generation of immunologists whose work eventually resulted in RTS,S. GSK biologist Dr Joe Cohen invented the vaccine, based on a protein first identified in the laboratory of Ruth and Victor Nussenzweig at New York University, and developed and manufactured it in laboratories in Belgium in the late 1980s.

Both the Bill & Melinda Gates Foundation and the World Health Organization (WHO) have a stake in the success of RTS,S and its eventual adoption as a definitive anti-malaria vaccine by African nations.

Dig a little deeper into the Nussenzweig couple’s twin biographies, and you’ll find a remarkable story of love and science. In fact, Victor and Ruth ’s planned visits to São Paulo aren’t a new start, but a long-delayed homecoming. He’s actually Brazilian born and raised, and received his training at the University of São Paulo School of Medicine.

It was there in the late 1940s that the young Victor Nussenzweig met Ruth, another medical student from a family of Austrian doctors whose Viennese family had escaped the Nazi terror in 1939.  Ruth persuaded Victor to join her in a research post under Prof. Samuel B. Pessoa the head of the Parasitology research group at the Medical School of the University of São Paulo.

young couple

Their first research work was with Trypanosoma cruzi, the agent of American trypanosomiasis, also known as Chagas disease. Eventually this led to the use of gentian violet in preventing the transmission of Chagas disease by blood transfusion.

But two events changed their lives. The first was Brazil’s 1964 military coup d’etat that led to an exodus of intellectuals and research talent that Brazil is only now recovering from half a century later. This prompted their move to NYU and Brazil’s loss became the world’s gain.

The second was the couple’s decision at NYU to start working with malaria, using two rodent parasites,  Plasmodium berghei and P.  yoelii that naturally infected a rodent found in a forest in Africa, found by Dr. Meyer Yoeli. A central discovery by Ruth was that gamma irradiated and attenuated sporozoites induced full protection against malaria in mice. This discovery shattered the prevailing dogma that a malaria vaccine was impossible to develop.

Research using sporozoites attenuated by irradiation, influenced many people worldwide and continues to do so. RTS,S is but one of many different vaccines being tested for malaria in humans, most based the circumsporozoite surface protein inspired by the work developed at NYU. The series of breakthroughs that he and his wife achieved during the 1960s, 1970s and 1980s, in understanding the biology of Plasmodium have now been taken forward by others to develop generations of commercial vaccines.

“I have now finished that research,” he says. “Now, I’m trying to develop drugs that will inhibit the kinases controlling the latent stage of the parasite.”

For two Brazilians who left their home country in the 1960s and went on to forge stellar careers in the United States, the most important objective is help the international efforts to rid humanity of the global scourge of malaria.

The Nussenzweig’s optimism about Brazil’s new research prowess is tempered with realism. They are well aware that Brazil needs to make up for the decades when native scientific research lost out because of the political uncertainty that followed their departure for New York in the 1960s.

mugshot“A research culture is difficult to grow,” concedes Victor Nussenzweig. “It takes time and it’s about more than just money. You need collaboration between competent, creative people. There are a lot of them in Brazil – nevertheless there’s not a lot of research conducted exclusively in Brazil that is published in leading-edge journals”.

It’s no coincidence, perhaps, that both early recipients of São Paulo Excellence Chairs awarded by FAPESP are for returning senior Brazilian scientists.  While the country is using its new economic prowess to attract international scientists to its shores, there is still a distinguished diaspora of Brazilian academics scattered across the upper echelons of European and US universities who need to come home first.

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