Obituary: Dr. Luigi (Gigi) Varesio

Dr. Luigi (Gigi) Varesio, a prominent specialist in innate immunity, passed away on Dec. 2, 2017 at the age of 67 after a courageous year-long battle with cancer. Gigi received his doctoral degree in 1974 from the University of Torino and continued there as a postdoctoral fellow until 1977. Under the tutelage of Dr. Guido Forni, Gigi worked on the role of RNA in regulating the immune response. In 1977, he joined the National Cancer Institute in the Laboratory of Immunodiagnosis and began his work on macrophages with Dr. Ronald Herberman and Dr. Hap Holden. In the late 70s and early 80s, he continued his collaboration with Forni’s lab and published many seminal papers, including one titled “Suppression of proliferative response and lymphokine production during the progression of a spontaneous tumor.” (Cancer Res. 1979). In the early 1980s, he joined the Biological Response Modifiers Program at the NCI labs in Frederick, MD where he established his own laboratory. His work in Frederick continued to focus on macrophage biology and, in collaboration with Dr. Ulf Rapp, he discovered that infection of mouse bone marrow or fetal liver with a retrovirus containing the v-raf/v-myc oncogenes resulted in the generation of mouse macrophage cell lines. This finding has been applied by labs around the world to generate cell lines from many different strains of mice, resulting in numerous scientific publications based on these lines.

Gigi remained at the NCI until 1995 when he and his wife’s desire to raise their daughters in Italy became too great and he returned to Genova where he was appointed as Director of the Laboratory of Molecular Biology at the G. Gaslini Institute. From 1995 up to 2017, the research of Gigi’s group in the Lab of Molecular Biology continued to focus on mononuclear phagocyte pathophysiology under conditions of hypoxia present in the inflammatory and tumor environment at both the cellular and the molecular levels. In this period, Gigi was also a pioneer in the characterization of molecular biomarkers in pediatric patients affected by neuroblastoma, demonstrating brilliant capabilities and innovative visions in this research field. He became responsible for the Genomic unit of the Gaslini Institute, which performs genome-wide analysis of mRNA, micro-RNA, and DNA, and for the Clinical Bioinformatic unit dedicated to data analysis. He set up and coordinated the Integrating Tissueomics Biobank (BIT)–Gaslini, which collects and centralizes Italian Neuroblastoma specimens (primary tumors/recurrencies, blood, bone marrow) correlated with clinico-pathological information in collaboration with the Italian Association of Pediatric Hematology and Oncology (AIEOP). He implemented a novel web-based platform for molecular and clinical data storage, integration, and diffusion as part of its participation to the European Network for Cancer Research in Children and Adolescents (ENCCA). In addition, he was the official Italian representative of the Neuroblastoma Biology Group at the International Society of Paediatric Oncology Europe Neuroblastoma (SIOPEN), responsible for coordinating biomarkers and risk factors definition and testing. Gigi’s group work led to major scientific accomplishments such as: i) the characterization of the transcriptome of monocytes and dendritic cells under hypoxic conditions, that was instrumental to define the adaptation of mononuclear phagocytes to low oxygen environment; ii) the definition of the hypoxic gene expression signature of neuroblastoma tumors that was an excellent probe for the hypoxic environment of the tumor mass; iii) the demonstration that the hypoxic status of the primary tumor represents a novel independent risk factor for neuroblastoma patients; iv) the design of a multi-signature ensemble classifier predicting neuroblastoma patients' outcome. In the last 3 years of career, he coordinated the NExT Project (Neuroblastoma, Exosomes and Treatment), a multicentric study focused on the identification of molecular markers of the response to induction-chemotherapy of high-risk neuroblastoma patients, critical for guiding a flexible and personalized clinical intervention. The rationale behind the project is another example of the cutting-edge ideas that have always been typical of Gigi’s clever mind.

Below are a number of personal recollections about Gigi from colleagues whose lives he touched.

Howard Young:  I joined the NCI Biological Response Modifiers Program in 1983 and was placed in Gigi’s section. I remember when Dr. Elisabetta Blasi called me in the lab to look at a culture flask containing bone marrow that had been infected by the v-raf/v-myc virus. Surprisingly and most interestingly, while there were no obvious adherent colonies in the flask, there were a number of very healthy appearing cells that were sticking to some cotton fibers that were in the flask.  This flask, or one similar, led to the development of one of the first immortalized mouse macrophage cell lines, GG2EE. I had the pleasure of co-authoring 7 papers with Gigi, and scientific discussions with him were always insightful and productive.

George Cox:  I had the good fortune of joining Gigi’s lab at the NCI in 1987, and worked closely with Gigi until his return to Italy in 1995. During that time, Gigi and his colleagues in the Macrophage Cell Biology Section of the Laboratory of Molecular Immunoregulation and, subsequently, the Laboratory of Experimental Immunology, continued to develop immortalized mouse macrophage cell lines by v-myc/v-raf recombinant retrovirus infection of bone marrow or fetal liver. Immortalized macrophage cell lines were established from strains of mice with genetically-determined differences in responsiveness to lipopolysaccharide/endotoxin. Gigi’s group also characterized the expression and function of interleukin-2 receptors on mouse macrophage cell lines as well as human blood-derived monocytes. We discovered differences in the expression profiles of various interleukin-2 receptor subunits on mouse macrophage cell lines compared with human monocytes. In addition, we demonstrated that mouse macrophages required interferon-gamma as a co-stimulus for interleukin-2-induced tumoricidal activity whereas human monocytes only required interleukin-2 for tumoricidal activity. The lab’s work on the regulation of cytokine- and picolinic acid-induced tumoricidal activity of macrophages led to research on the involvement of nitric oxide in macrophage function.  Gigi’s group went on to identify and characterize an hypoxia-responsive element that mediates a novel pathway of activation of the inducible nitric oxide synthase promoter by picolinic acid producing nitric oxide, critical for the functional activity of macrophages. Later, Gigi and his colleagues reported the expression and regulation of inducible nitric oxide synthase in interferon-gamma-treated murine macrophages cultured under hypoxic conditions.

Elisabetta Blasi:  As a recipient of an NIH-NCI Fogarty Fellowship, I joined Gigi’s laboratory in Frederick, MD (USA) in July 1982, when he was Section Head, and I remained there for 4 years. I will never forget the scientific rigor of Gigi, his challenging but also affectionate supervision, his enthusiasm and the reliance he transmitted to each of us, no matter the role or the position; summer students, technicians, senior investigators, full professors, etc. All individuals received full consideration by Gigi. The atmosphere in the lab was always positive also because, behind the science, Gigi often made terrific and unforgettable jokes, which rendered our lab life particularly amusing/joyful. The great example of generosity and profound humanity together with the scientific passion experienced under Gigi’s training have been crucial for my return to Italy and will remain in my heart for life.

Danuta Radzioch: Gigi had been a fantastic supervisor for several postdoctoral fellows at the Frederick Cancer Research Facility (FCRF).  I, currently a Professor at the Department of Medicine and Human Genetics at McGill University in Montreal, Canada) had the privilege to be one of them.  The laboratory work and the social life of his laboratory, which was filled to capacity with trainees and visiting scientists, were never boring. Gigi was an inspiration for us; he taught us to think independently, to be fearless, and to never give up when facing problems. His teaching methods were not conventional since he was always our friend first and boss second. There was never any doubt that he wanted only the best for our professional careers and personal lives. I worked under Gigi’s supervision from 1984 until 1989, but even when I got a position as an Assistant Professor at McGill following the completion of my training at the Biological Response Modifiers Program (BRMP) at the FCRF, I continued coming to Frederick every summer for the next few years. Together, we have published 19 papers. Moreover, contact among the former postdoctoral fellows from Gigi’s laboratory (Dr. Elisabetta Blasi, Dr. Arnaldo Carbone, Dr. Maria Carla, Dr. Tiziana Musso, Dr. Enzo Bonvini, Barbara Bottazzi, Luca Gusella, Juan DeSanctis), visiting professors (Dr. Alberto Mantovani, GP Tonini, Guido Forni) and the technician Mike Clayton continue to this day. Whenever and wherever we meet, we cherish the memory of the time we had the opportunity to work with Gigi. He was a great friend, always ready to help or engage in a prank that would teach us something important or simply make us laugh until we cried. We all remember his most famous expressions such as “breathing is optional”. We have been quoting Gigi for decades! We will never forget how wonderful scientist and friend he was to all of us. He will live in our hearts forever.  

Maria Carla Bosco Personally, I met Gigi in late 1990 when I joined the Macrophage Cell Biology Section and followed him back to Genova in 1997, participating in most of his research projects and co-authoring several seminal papers with him. He has been for me a guide and an important person of referral because of his enthusiasm, geniality, and ability to understand and deal with complex scientific problems. During his professional career, his ability to give the right suggestions and to lead valuable research projects combined with his strong personality, ambition, and integrity made him a valid mentor and an esteemed supervisor for many young scientists in the lab contributing to strengthen their passion for science.

Antonio Sica:  My scientific growth led me to join the NCI biological response modification program in 1990, in the laboratory run by Dr. Howard Young. At that time, I was also lucky enough to meet Gigi Varesio and to appreciate his intellectual acumen, always characterized by great intuition and originality of ideas. Gigi has introduced me to the concept of microenvironment and to the significance that the microphysiology of tumor tissue plays in the modulation of the immune response. This scientific input is still today a strong background on which the scientific community and my group in particular, develop new ideas and research projects. I deeply thank Gigi for his sincere friendship and for giving me the opportunity to share with him a great scientific and human experience.
Juan B. De Sanctis: One of the most significant characteristics of Gigi was his kindness. Gigi was a friend rather than a strict supervisor. Dr Igor Espinoza Delgado (died 2011) and I (JBD) came from Venezuela to learn macrophage response in cancer and lipid metabolism. Gigi and his always ready to help postdoc in his laboratory, Danuta Radzioch, were always there to support us. Igor became a successful oncologist and I came home to direct the Institute of Immunology at the Faculty of Medicine, Universidad Central de Venezuela. Gigi flew twice to Caracas and had a little time to spend at the local beaches, a pleasure he always remembered.

Dan L. Longo: It was a great privilege for me to work with Gigi and the amazing and talented people he drew to his laboratory at the NCI BRMP.  Scientific discussions with Gigi always led to new testable hypotheses that he and his colleagues were quick to act on.  His scientific sophistication was matched by a deep appreciation of music and the arts.  I recall that a major criterion he applied to the purchase of a new car was whether the engine ran sufficiently quietly to minimize aural interference in the classical music he used to ease the burden of his commute.  The advances that he and his colleagues made in understanding monocyte and macrophage biology form the foundation of the current advances being made and their application to treating human disease.

All of us, no matter whether mentioned here or not, are fortunate individuals to have interacted with Gigi during our careers.  And so together we say:
Thank you Gigi! Your memory will be in our hearts forever.