Alberto Mantovani: facciamo scienza sulle spalle dei giganti

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In occasione del conferimento del Premio Robert Koch 2016 ad Alberto Mantovani e Michel Nussenzweig, Mantovani ha risposto alla Laudatio del premio Nobel per la medicina 2011 Jules Hoffmann con un discorso che ricorda i "giganti" della medicina che hanno aperto la strada alla via immunologica contro il cancro, da Rudolph Virchow a Elie Metchnikoff. Lo riportiamo qui di seguito:

Bernard de Chartres in the 12th century was probably the first to coin the metaphor that we are dwarfs on the shoulders of giants, based on the greek myth of  Orion and Cedalion. This is not  the way I felt and feel receiving the news of the Robert Koch Award: I feel like being a very small dwarf on the shoulders of big giants including previous Robert Koch Awardees.  My thought and gratitude today goes to my mentors and Maestros, and I include in that category my technicians and young fellows. I also think of my beloved wife Nicla, who at times may have been jealous of my passion for a fascinating  lady called Immunology. 

Giants.  I will start and conclude my reflections sitting on the shoulders of some of these giants. Rudolf Virchow is one of them and he is usually referred to as the first to perceive a connection between inflammation and cancer. Indeed, the title of a  review that Fran Balkwill and I authored  in The Lancet in 2001 is “Inflammation and cancer: back to Virchow?” (I should say that the original version of the title which I drafted was without a question mark). I specialized in Oncology in the ‘70s and the reference textbook at the time was “Cancer Medicine” by Jim Holland. No mention was made there of a connection between inflammation and cancer and of the tumor microenvironment. Inflammation is a manifestation of mechanisms of innate immunity, with a pivotal role of phagocytes, macrophages in particular, and I will get back to these cells in a few moments.

Another giant. Paul Erhlich is a founding father of modern Medicine and Immunology with his amazing forsight of antibodies. He and other founding fathers were observing the tools of immunology, such as antiserum therapy developed by Kitasano and Behring here in Germany, changing the course of dreadful diseases such as difteria. They dreamed of using the tools of immunity to fight cancer. Thus, generations of physicians and scientists have dreamed of using the power of our immune system to fight cancer, prompted by the key contribution that vaccinology and immunology have given to double our life expectancy in less than a century. Efforts along this line lead to what I would consider no more than proof of principle clinical evidence, a lot of frustration and widespread skepticism among oncologists.

My own connection to the dream stems from my interest in macrophages and my training with Bob Evans at the Chester Beatty Research Institute in London. In the late 1970s, studying macrophages  infiltrating mouse metastatic tumors and human tumors, I found that these cells promoted tumor growth, running against current views of the time. Jules Hoffmann in his laudatio has summarized how this interest of mine in innate immunity has developed into the dissection of  the words of immunity that we call cytokines and molecular pathways of innate immunity. For instance, the view that macrophages promote cancer lead us in the early ‘80s  to search for macrophage attractants (now called chemokines) produced by cancer cells.

In the same year 2001, when Fran Balkwill and I published our review in The Lancet on the connection between inflammation and cancer, in a classic fundamental paper in Cell, Doug Hanahan and Bob Weinberg crystallized the essence of being a tumor in 6 hallmarks: this seminal  publication crystallized a prevailing cancer cell-centric view of the essence of cancer. I, and immunologists at large, felt otherwise.  In the last 16 years we have witnessed a change in the accepted paradigm of the essence of cancer, crystallized once more by Hanahan and Weinberg in a review in Cell in 2011. The new version of the paradigm includes the microenvironment, the ecological niche, as a key component of cancer. In brief, development of a clinically observed tumor  is associated with the recruitment of corrupted policemen,  macrophages, and other white blood cells, which help cancer to progress. Concomitantly, the directors of the adaptive immunity orchestra, the T cells, are put to sleep; they are like a “Ferrari” with many brakes on. The brakes we call “chekpoints” ,  and the corrupted policemen help holding the brakes on.

The change in paradigm together with progress in identifying  the cells and molecules involved in immunity have lead to a revolution in the fight against cancer. We use antibodies, cytokines and anti-cytokine molecules to treat patients and to protect them from toxicity; we release brakes called checkpoints; we are learning how to stop corrupted policemen and how to reeducate and increase in number and arm the army of our soldiers. 

I consider myself a person with many previleges and one of them is seeing and being part of the initial fulfilment of a dream, a dream of the founding fathers and of many, including myself, the dream to use the power of immunity to fight cancer.

I would like to conclude with two reflections on science and society. The first relates to developing countries. Thanks to progress in the control of infectious disorders, cancer is now a major health problem in the developing world. Cancer diagnosis and treatment are extremely expensive, and more so are the immunological tools. We should start thinking of strategies aimed at sharing. An impossible dream? I served in the Board of the Global Alliance for Vaccines and Immunization (GAVI: remember GAVI is not only an interesting italian wine) and so did Stefan Kaufmann. The dream we had of sharing human papilloma virus vaccination, rooted here in the work of Robert Koch Awardee Harald zur Hausen is becoming true thanks to GAVI. Let us dream about sharing appropriate cancer treatments including immunological tools .

Back to giants, Elie Metchnikoff, and a second reflection. This year is the centennial of Metchnikoff  death. Metchnikoff is the founding father of studies on macrophages and cellular immunity. The fact that the honor of the Robert Koch Award is bestowed on me on Metchnikoff centennial has a special emotional value for me, though in cancer Metchnikoff policemen get corrupted. Metchnikoff, a Russian/Ukranian, culturally French, lived at a time of profound divide between France and Germany which included immunological theories. Reading a recent biography of Metchnikoff, I was struck by the fact that these giants, he, Paul Ehrlich and Robert Koch, having fiercely opposed scientific views and living in countries  dominated by hostile feelings, respected each other, hosted each other, were friends. These giants remind us that we, scientists and medical doctors, are called to serve as bridge builders, to build bridges of respect, tolerance and peace, starting from our own laboratories and clinics.

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