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AstraZeneca Traveling Lectureship Award: A Milestone in My Professional Career As a Toxicologist
By José E. Manautou, 2008 AstraZeneca Traveling Lectureship Award Recipient
Dr. José E. Manautou, Associate Professor of Toxicology and the Marlene L. Cohen and Jerome H. Fleisch Scholar at the University of Connecticut in Storrs, is the recipient of the 2008 AstraZeneca Traveling Lectureship Award. In this article, Dr. Manautou shares his experiences and discusses the new opportunities for collaborative research with European scientists.
My sabbatical work at the Academic Medical Center of the University of Amsterdam in 2003 gave me a unique perspective on the quality of research and dedication of scientists in Europe. It also gave me an opportunity to publish scholarly work and establish long-term relationships with scientists in The Netherlands. I viewed the AstraZeneca Traveling Lectureship Award as an opportunity to further expand my network of collaborators, to share research ideas, and to engage in an open dialogue with scientists in Europe on research and regulatory issues. Developing the “ideal” itinerary for an AstraZeneca lectureship series was a daunting task since Europe houses a large number of highly accomplished and recognized scientists in areas of research that are of great interest to me. After much deliberation, I came up with a list of scientists with diverse expertise representing industry, academia, and research institutes. I was very fortunate to have received highly enthusiastic endorsements from all scientists approached to serve as hosts on my award application. The prospect of future collaborative work with European colleagues was an important deciding factor when applying for this award.
My research interests are on biochemical and genetic determinants of susceptibility to liver toxicants. The focus of the research in my laboratory is on the role of drug transporters in the disposition of hepatotoxic agents and how changes in the expression and function of these transporters alter susceptibility to drug hepatotoxicity. This is an area recognized for its emerging importance in toxicology by scientists in academia, industry, government, and other regulatory bodies. My laboratory also continues to study the mechanistic basis of protection against acetaminophen hepatotoxicity by treatment with peroxisome proliferators. We recently employed a genomic approach to identify changes in gene expression mechanistically relevant to the protection afforded by the peroxisome proliferator clofibrate. We determined that Vanin-1, a gene encoding a protein involved in the synthesis of cysteamine and cystamine, is the most significantly induced gene in mice afforded hepatoprotection by clofibrate treatment. Cysteamine and cystamine are potent antioxidants known to prevent acetaminophen hepatotoxicity in rodents and humans. Collectively, my research interests encompass areas of investigation that are of great interest to European scientists.
From September 1–17, 2008, I visited Sweden, Switzerland, and Hungary. Peter Moldeus, Global Vice President for Safety Assessment at AstraZeneca R&D suggested a visit to their facilities in Södertälje for a seminar presentation and discussions with his toxicology group. Some of Peter’s earlier work was on acetaminophen toxicity. Our discussions centered on idiosyncratic drug hepatotoxicity and transporter protein function. Peter also arranged a half-day visit with Dr. Magnus Ingelman-Sundberg at the Karolinska Institute, where we discussed common research interests on the interaction between hepatocytes and Kupffer cells and the role of Kupffer cell function in drug hepatotoxicity.
In Zurich, I visited the laboratory of Dr. Bruno Stieger. He is the head of the research laboratory of the Institute of Clinical Pharmacology and Toxicology at the Department of Medicine, University Hospital in Zurich. He is a world-renowned expert in liver transporters. My seminar and subsequent discussions centered on the expression and regulation of drug transporters in response to acetaminophen-induced hepatotoxicity in mice and humans. Bruno provided some perspective on factors regulating drug transporters in different models of liver disease and on the functional consequences of such changes.
The last visit on the first segment of my AstraZeneca lectureship itinerary was to SOLVO Biotechnology in Budapest. Dr. Péter Krajcsi, Chief Scientific Officer of SOLVO, served as my host. This is a privately owned biopharmaceutical company that specializes in the commercialization of membrane transporter technologies. Following my seminar presentation on expression and regulation of liver transporters, Peter and his group shared some of their recent work on the effect of lipid composition on membrane transporter function and some of their latest commercial technologies and tools available to assess transporter function. While in Budapest, I also visited the laboratory of Dr. Balázs Sarkadi at the National Institute of Haematology and Immunology. I learned about his most recent work on the role of transporters in progenitor cell differentiation.
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| José Manautou and Philippe Naquet; Marseille Vieux Port in the background |
The second set of the AstraZeneca lectures took place during the last two weeks in November 2008. I visited France, Portugal, and England. On November 17, I visited the laboratory of Dr. Philippe Naquet at The Centre d’Immunologie de Marseille-Luminy (CIML). Philippe’s most significant contribution has been the discovery of Vanin genes, the identification of their enzymatic function, and their physiological role. During the seminar presentation in Marseille, I described our work on the hepatoprotective actions of peroxisome proliferators and the results of our gene array studies indicating that Vanin-1 induction might be relevant to preventing acetaminophen hepatotoxicity. Extensive discussions on the association between Vanin-1 expression and hepatoprotection took place, and collaborative studies combining expertise and resources of our respective laboratories were planned. I am happy to announce that some of these studies are currently underway.
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| José Manautou, Carlos Palmeira, and Anabela Simões at Coimbra University |
In Portugal, I visited the laboratory of Dr. Carlos Palmeira at University of Coimbra. I have known Carlos for a number of years through SOT and have discussed with him in the past common research interests. My research presentation at Coimbra covered some of our recent data on the potential role of multidrug resistance protein 4 (Mrp4) in conferring cellular protection against chemical-induced oxidative stress. Some of Carlos’ research interests are on the role of oxidative stress and mitochondrial dysfunction in the pathogenesis of hepatic diseases. We had in-depth discussions and planned a series of experiments to investigate if induction of certain transport proteins prevents oxidative stress-induced mitochondrial dysfunction. These studies also are currently underway. My final visit was to the AstraZeneca Alderley Park in Cheshire, England.
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| José Manautou, Abby, and Emma Roberts at Andy and Ruth Roberts’ home |
This was not simply a courtesy visit as required by the award. Ruth Roberts served as my host during my visit to Alderley Park. I have known Ruth for many years, and we also share common interests in biochemical and molecular modes of action of peroxisome proliferators. The safety assessment unit at Alderley Park, although relatively small, has a very active group of toxicologists/molecular toxicologists. My presentation and follow-up discussions focused on drug transporters and their role in drug hepatotoxicity and the current efforts at AstraZeneca in integrating drug transporter research in drug development and safety assessment.
All my hosts were extremely gracious, extending hospitality above and beyond my expectations, ensuring that my visit to their respective cities was memorable and enjoyable. Something that became very evident during these trips is that “toxicology is a small world after all.” Just by chance, I was on the same flight from Stockholm to Zurich with Birgitta Lewander and Torbjörn Malmfors. They were on their way to the 2008 RAAS Risk Assessment Summer School in Bodensee, Germany. Then, just a few days later, I ran into Nancy Monteiro and Jim Riviere at the Central Train Station in Zurich. I was catching a train to the airport as they arrived to the city for a conference on nanotechnology.
I would like to emphasize that all these scientific exchanges and new collaborations would have not been possible without this award. AstraZeneca and Peter Moldeus are to be commended for going beyond maintaining this award by increasing its monetary value in 2008. This commitment to the AstraZeneca Traveling Lectureship Award is being sustained despite the current global economic climate. I hope that other corporations would follow suit and help SOT to establish similar awards that will enable its members to embark on lectureship series in developing countries, where resources to attract toxicology scholars for seminars and scientific exchanges are very limited. This would be a significant step in further globalizing the mission of SOT. Finally, I have to extend my gratitude to my Dean Robert McCarthy and my Department Head John Morris for providing supplemental travel support and for encouraging me to apply for this award. As a toxicologist, it is a great honor to be among the list of past recipients of this prestigious award. The numerous experiences, new contacts, and exposure I received during my time in Europe are invaluable and will have a long-lasting impact on my research and professional career.
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