On the scientific life of Francesco Pietra

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 In these days of threat to the human kind, I would like to bring back my two readers to my book of two decades ago "Biodiversity and Natural Product Diversity" Elsevier, Tetrahedron Organic Chemistry Series Volume 21, 2002, where one reads that "The Earth is becoming overpopulated and globalization is undergoing a major upheaval in our time. These are causes of an even redistribution of species" (page 269).

What that means? The answer comes from (i) "The theory that a robust ecosystem  is tied to a high biodiversity (species redundancy) is gaining experimental support ... (page 302), in the light, however, that "Biodiversity is difficult both to define and measure. Central to the issue is the concept of species, which has proved most elusive to generations of biologists" (page 3) and (ii)"the survival of the fittest, which was at the basis of Darwin's thoughts and has never been disproved" (page 5).

In plain words, survival of the fittest occurs for all species and also for viruses. RNA viruses (retroviruses) can also possibly mutate faster than allowed by the usual clock, exploiting their mechanism of integrating their newly built DNA into that of the host cell. Which also implies that the host cell may loose control of its DNA.

When the new virus will vanish from humans, thanks to vaccines, we should not forget that it will remain with bats and possibly also with pangolins and other wild mammals, ready to jump again into human cells. Toward a robust ecosystem Earth, we  should rethink about globalization, doing all that we can to avoid redistribution of species. This requires a revolution in our lifestyle, which should start now. Otherwise it has no chances. Men forget easily.




The above picture illustrates the structure of the acid-sensing ion channel cASIC1a, which is involved in ischaemic neuronal injury (F. Pietra, Chemistry&Biodiversity, 2015, 12, 350-357). What I carried out was the elucidation, as alpha helices, of the initial (highlighted in red) and final parts of the protein chain (highlighted in green). It is hoped that inhibition of ASIC channels, such as by Tarantula toxins, might relieve from pain upstream of opiate systems, thus avoiding the use of opium drugs.




The only lively memory of the primary school is from Professor Pescarmona, the Latin and Italian teacher in Moncalvo Monferrato. A war veteran who had lost his lower legs in Russia. What I leaned from him paved the way to my training at the Liceo Scientifico Enriquez, in Livorno, where I learned how to set a scientific project from the Latin scholar Vincenzo Courier, how to treat it from the mathematician Emilio Ceccarelli, and how to run a scientific institution from the Dean, the German scholar Achille Radaelli. It was Emilio who stimulated me to complete the  last two years in one only, and thereafter that became a close friendship. We were both passionate divers.



Out of the university courses, it were only the lectures in physical chemistry and electrochemistry by Antonio Foffani that left an indelible mark with me. Otherwise, that was a dull period. My interest in chemistry resurrected under the guidance by Antonino Fava as to the mechanisms of organic reactions, built on the mathematics that I had learned from Emilio. But the breakthrough was the 1965 textbook "Basic Principles of Organic Chemistry" by J.D. Roberts and  M.C. Caserio, which opened my mind to a combined classical and post-modern view of organic chemistry founded on thermodynamics. That, I must say, could be built on the thermodynamics that I had received from Antonio Foffani, and since then I never renounced to first examine all problems from the thermodynamic point of view.



For my Libera Docenza in Chimica Organica Superiore, the equivalent of the German Privatdozent, I received support by J.F. Bunnet, the great physical organic chemist founder of the Accounts of Chemical Research. He wrote  (To whom it may concern) "On the basis of Dr. Pietra's research contributions, I would consider him well qualified  for appointment as associate professor (with tenure) in the University of California". Which was followed by the evaluation by the Italian committee "Tutta la produzione scientifica del Pietra e' impostata e condotta con grande rigore scientiifico. I risultati da lui ottenuti  hanno avuto una notevole risonanza internazionale, come dimostrano inoltre le numerose citazioni di essi in qualificati libri e rassegne internazionali". Regrettably, this fundamengtal step in the scientific career does no more exist in the Italian system.

Shortly after those (for me) great days, on the stimulation by colleagues of chemical engineering in Pisa, I applied for the position of professor of Physical Organic Chemistry. I got a phone call by Antonio Foffani, to my surprise member of the examination committee, to meet him in Bologna at the Ciamician. Things were running, the Faculty in Pisa was already organizing for my new position, but my application did not go on. That would have made my life easier, both in my family and with the many students carrying out their thesis work in my lab. Shortly after that I had to leave all them to earn my bread elsewhere instead of continuing with physical organic chemistry.

In the meantime,  in the group of Derek Barton at the Imperial College in London, my eyes were opened to the big organic chemistry. No telephone in Barton's office, every meeting was a concentration of attention and ideas, in the lovely atmosphere of South Kensington and the nearby Chelsea, where I had rented a small flat with my wife and my little daughter.The tennis court was 5p, squash was 5p, everything at the college was 5p.

My work continued with publications on Chemical Communications and other journals of the Royal Chemical Society, as well as on the Journal of the American Chemical Society. For this activity I got a call as Invited Lecturer of the British Council for the year 1974 throughout Scotland and northern England.



 With the Chair of Organic Chemistry at the University of Trento, I was given all great means needed to start research on marine natural products, a branch of organic chemistry that was already in my dreams while at the Universita' di Pisa, where I had no means enough for that.

I started a systematic search of marine organisms that were likely to entail novel natural products. This brought me to visiting marine stations in Europe and in coral reef areas, mainly from the great network of the French oceanography. To secure samples of marine invertebrates and algae, I turned my leisure activity as a diver into professional activity, why organic chemistry remained at the forefront for structure elucidation of the new natural products, which required organic synthesis in combination with the spectroscopic tools. A lively period in a team of young coworkers attracted to Trento from the universities of Naples, Bologna (Ciamician) and Padua and skilled technicians. This work was more connected than before with daily life, and brought me to close relationships with the research pharma.

My diving included the Stazione Zoologica di Ganzirri, the Station Zoologique de Villefranche, the INSERM 303 Villefranche-sur-Mer, the Station Marine d'Endoume a Marseille, the Laboratoire Arago at Banyuls-sur-Mer, the Station Biologique de Roscoff,  the Station Biologique Archachonne, the Hawaii Institute of Marine Biology at Coconut Island, the ORSTOM Centre de Noumea Nouvelle Caledonie, The south coast of Livorno and the Elba Island. All that besides collecting samples by dredging or along the coast, in pioneering work on marine fungi, brachiopods, and marine ciliates, the latter in a long collaboration with professor Fernando Dini at the University of Pisa.

There, I conceived what was a breakthrough in the thinking about natural products: unifying concepts about marine and terrestrial natural products, F. Pietra "Structurally similar natural products in phylogenetically distant marine organisms, and a comparison with terrestrial species" Chemical Society Reviews 1995, 24, 65-71.



In the year 1998 I was appointed to the Centro Linceo Beniamino Segre, at the Accademia Nazionale dei Lincei in Rome. In the same year I was awarded the Maria Teresa Messori Roncaglia ed Eugenio Mari Chemistry Prize by the Accademia Nazionale dei Lincei. It was emotional and heartbreaking in that day in the Quirinale palace shaking hands with the President of the Republic, Oscar Luigi Scalfaro. 

During the Lincei period in Rome I frequently met professor Alessandro Ballio, who had silently a great impact on my scientific life. I only learned lather that he was member of the evaluation committee for my chair and that he supported my nominations above. Besides the many enlightening discussions about my research while walking around the gardens of the Accademia. 

There, I engaged in a major writing, F. Pietra “Biodiversity and Natural Product Diversity” (Tetrahedron Organic Chemistry Series, Volume 21); Elsevier, Oxford 2002. This book offers a new perspective on natural products, no more from only the chemical and biogenetic points of view, but also linking them to taxonomy and genetics as well.



I delivered named lectures at meetings, universities and pharma research centers, including the Gordon Conferences and a special meeting, where I represented Italy for the chemistry of biologically active natural products: the Marconi Symposium in Sydney and Melbourne in the year 1995. The other ones I can remember had place at the ETH Zuerich (Prof Heinrich Zollinger) 1965 "Isotope effects in the nucleophilic reactions of protic amines with nitro-activated substrates". La Sapienza Universita' di Roma (Prof Gabriello Illuminati) 1965 "Meccanismi di reazioe di sostituzione nucleofila aromatica. Universita' di Bari (Prof E. Todesco) 1970 "Chimica di troponoidi". University of Dundee (Prof R. Foster) 1974. Strathclyde University Glasgow (Prof P.L. Pauson) 1974. Durham University (Dr M. Crampton) 1974. University of Liverpool (Prof C.W. Rees) 1974. UNESCO European Intensive Course, Banyuls-sur-Mer, August-September 1982. CNRS Gif-sur-Yvette (Professors Pierre Poitier and Derek Barton) 1985. IRD, Noumea 1995 "Capitalizing on natural product diversity of coral reefs".   Table Ronde sur la Caulerpa taxifolia, Carrefour Universitaire, Nice (Prof A. Meinesz) 1991. Seventh International Symposium on Marine Natural Products, Capri (Prof L. Minale) 1992.  La Sapienza Universita' Roma (Prof A. Ballio) 1992. Universita' di Camerino  1994. Marconi Symposium, Melbourne and Sydney,  as a representative of Italy for the Chemistry of Natural Products 1995. The University of Melbourne (Dr Robert Capon) 1995.  Pharmacia-Upjohn, Nerviano  1996. Antibioticos SpA, Milano 1996. Lepetit, Gerenzano, 1996. Boeringer Ingelheim Pharmaceuticals, Ridgebury Conn, 1998 "Chemistry in the chemistry of natural products. Universita' di Siena (Prof C. Rossi) 1998. Gordon Conference on Marine Natural Products, Ventura, Cal, 1998 "Secondary Metabolism and Genetics of Marine Free Living and Metazoan-Associated Microbes". Sigma Tau Pharmaceuticals, Pomezia 1999 "Diversita' molecolare dalla biodiversita' marina. 22nd IUPAC International Symposium on the Chemistry of Natural Products, Sao Carlos, Brazil, 2000 "Evolution of the secondary metabolite vs, evolution of the species". Perspectives of the Chemistry of Natural Organic Products, Istituto Lombardo Accademia di Scienze e Lettere, Milano 2002 "Stereochemistry and phylogeny". Accademia dei Lincei, Rome  1994. Symposium on Chemistry and Biology: The Transition Bettween the Two Centuries "From the Phoenicians to modern genetic manipulations: the history of organic natural products" 2004. IRD, Noumea, Nouvelle Caledonie, Symposium on the Conservation of Coral Reefs, 2006 "Capitalizing on natural product diversity of coral reefs".



I acted as a referee for the appointment to chairs and the evaluation of PhD theses for Australia (Monasch University, Melbourne), France (Universite de Nice Sophia Antipolis), New Caledonia (Universite dela Nouvelle-Caledonie) and India (Banbalore University).

I spent most of my time in supervising the doctoral thesis in chemistry of a number of students at the University of Pisa, and I was rewarded by their fresh approach  to the problems. Most of them had their thesis work published, which served them to start from a higher position in the chemical industry. A couple of them, Gino and Vittorio, reached soon top positions in the pharmaceutical industry in Europe and the States. But I was also deeply disappointed on that matter viewing Michele D'Ambrosio stopped at the level of "Ricercatore".  Michele was the main author of the most lasting work of my group at the University of Trento and the sole of my coworkers that had experienced the big chemistry in the States, having spent one year at the Scripp. It still grieves me to see elsewhere people having reached the level of "Professore Associato" without even attending regularly their office.

I also supported developing countries, in bringing to the Thèse d'État at the Université Cheikh Anta Diop, Dakar, a Senegalese student, Ibrahima N'Diaye (the son of a fisherman), following four years of research in my lab at the University of Trento. That at the Faculty in Dakar was a charming day for me, seeing the appreciation by the Dean and his colleagues for the contribution of my University of Trento for science in  Senegal. With my letter of support to the Center in Burkina Faso, Ibrahima was appointed Maître de Recherche at the Université Cheikh Anta Diop in Dakar.

As a member of the editorial board of two journals, I am often assigned the heavy task of reviewer of  submitted manuscripts.



I retired from the university before the terms, doubly disappointed. Above all, by my failure to establish by the Faculty of Science in Trento to found a full degree in Biochemistry. Unique among developed (and most emerging) countries, the Italian university still does not offer such a fundamental degree. Left to historians, with all original letters of support by scientists from all over the world, is my booklet entitled  "The Short Life of the Institute of Chemistry at the University of Trento", 2008. It exists as a single copy in the library of the Accademia Lucchese di Scienze Lettere e Arti. But also disappointed by my failure to raise Michele at an appropriate university level.

Out of my 390 scientific publications, the last ones (33) have been carried out since I was elected at the Accademia Lucchese. The start was a quantum mechanical solution of the conundrum of mutarotation, present with isocolchicine and absent with the anti-gout agent, colchicine.

Then the work continued with elucidation of the pathways of dioxygen through proteins, culminating with the discovery, through quantum mechanics - molecular mechanics simulations, of the chemistry that develops when when dioxygen gets to the diiron active center of the ferritins. Thus, a new mechanism has been discovered for dioxygen activation with ferritins, which are the regulatory proteins of the ferrous content with nearly all living organisms (F. Pietra, A New Route for Dioxygen Activation Uncovered from Quantum Mechanics Investigations of Xray-Diffraction Captured Intermediates of the Ferroxidase Reaction of Ferritins from Gram-negative Bacteria, Advanced Theory and Simulations, 2020).

Not forgetting my long-term interest in antitumoral agents. Thus, our discovery, in the year 1987, of the sarcodictyins, antitumor agents from a Mediterranean coral, led to the US Patent 5,869,514 with Pharmacia & Upjohn. Now, simulations on the mainframes at the CINECA have allowed to propose the least-energy structure of the complex of sarcodictyin A with tubulin has been unraveled (F. Pietra "Fighting cancer with microtubule-stabilizing agents: a computational investigation of the complex between β-tubulin and the microtubule-stabilizing, antitumor marine diterpenoid sarcodictyin A" Structural Chemistry, 2019, https://doi.org/10.1007/s11224-019-01440-8.

My interest in antitumor agent continues now with the agelastatins, isolated by deep-water dredging from a sponge of the South Seas several years ago (M. D'Ambrosio, A. Guerriero, C. Debitus, O. Ribes, J. Pusset,  S. Leroy, F Pietra "Agelastatin A, a new-skeleton cytotoxic alkaloid of the oroidin family. Isolation from the axinellid sponge Agelas dendromorpha of the Coral Sea" J. Chem. Soc., Chem. Commun., 1993, 1305-1306). The bioactivity of the agelastatins has been recently patented by both the Mayo Foundation for Medical Education and Research,against brain tumors (Treating brain cancer using agelastatin a (aa) and analogues thereof, PCT/US2013/064605, Apr 17, 2014) and the Massachusetts Institute of Technology (Potent agelastatins as modulators for cancer invasion and metastasis WO2018209239A1 and several other patents focusing on the treatment of blood cancer).



Financial support to my research work came from C.N.R, Rome, the Universita' di Trento, the Provincia Autonoma di Trento, IRST Trento, Regione Toscana, MPI Progetti di Interesse Nazionale,  MURST Progetti Nazionali, MIUR Rome, CEE  LIFE DG, Castalia SpA Rome, NATO Bruxelles, and Pharmacia-Upjohn, Starting from paper nr. 23, in the above series of 33, financial support was in the form of access to mainframes, generously granted to me at the Accademia Lucchese by CINECA through the ISCRA initiative. I warmly thank all them, as well as the various foreign organizations that supported my work in their laboratories. These include the Imperial College, London, Gorlaeus Laboratories of the University of Leiden, the Station Marine d'Endoume of the Universite de Marseille, the Laboratoire Arago, the Station Biologique de Roscoff, the Station Zoologique Villefranche, the INSERM Villefrance, ORSTOM-CNRS Noumea. IRD Noumea, the Hawaii Institute of Marine Biology, Oahu.



Except for a break as a fiction writer (F. Pietra “The old man and the roading dog” Gray's Sporting Journal Augusta, Georgia, 2005, 30, 1316, a novel that represents an insight into the psychology of the pointing dog and his prey) all of them deal with health or environmental problems.

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