On the scientific life of Francesco Pietra

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Nearly all life grows on water-soluble ferrous ion, which, however, becomes easily oxidized by dioxygen, generating toxic products. Therefore, to keep things going, regulatory proteins have evolved that keep ferrous ion at non toxic levels. These proteins, which are called ferritins, are present in nearly all organisms. The above picture illustrates the structure of a new intermediate in the activation of dioxygen by the ferritins (in this stick representation, carbon backbone in gray, hydrogen-atoms in white, oxygen atoms in red, nitrogen atoms in blue, iron ions as spheres; dioxygen is shown as a stick between the two iron ions). Recourse to broken symmetry was key to this discover, and the resulting spin density is visualized in scaled gray. This work appeared as F. Pietra "A new route for dioxygen activation uncovered from quantum mechanics investigations of X-ray-diffraction-captured intermediates of the ferroxidase reaction of ferritins from Gram-negative bacteria" Advanced Theory and Simulations 2020, 1900253 DOI: 10.1002/adts.201900253 https://onlinelibrary.wiley.com/doi/abs/10.1002/adts.201900253

 

 

PRIMARY and HIGHER SCHOOL

The only lively memory of my primary school is of Professor Pescarmona, a war veteran and  Latin teacher in Moncalvo Monferrato, where my family had migrated during the war. Pescarmona had lost his lower legs in Russia but saved a lively aptitude that was our major comfort during those troubled days. He was also a great Latin scholar so that what I learned from him paved the way to my training at the Liceo Scientifico Enriquez, in Livorno. There, I learned how to set a scientific project from the Latin scholar Vincenzo Courier, how to work out it from the mathematician Emilio Ceccarelli, and how to run a scientific institution from the Dean, the German scholar Achille Radaelli. Emilio stimulated me to complete the last two years in one only, and thereafter we became close friends. Underwater fishing was our passion along the southern coast of Livorno. A skill that turned out useful later, with my involvement in the chemistry of marine natural products.

 

UNIVERSITY AND EARLY CAREER

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 great school of Antonino Fava for reaction mechanisms, built on the mathematical skill that I had from Emilio Ceccarelli. 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. It was the school of Foffani and Fava that let me appreciate so much this book, which I mastered in a lovely small flat near the boathouse in Viareggio, where my father had taken a post-retirement job. Those were perhaps the happiest days in my life, no trouble was yet at the horizon.

 

The LIBERA DOCENZA and the CENTRAL CAREER

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 fundamental step in the scientific career, which weighed more than a chair and was mandatory to keep tenure at the university, does no more exist in the Italian system. Abolishing it was one of the various great mistakes by the political class that turned out to be deleterious for the Italian university.

Shortly after those 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 building. Things were running, the Faculty in Pisa was already organizing for my new position, but the lobby barrier could not be overcome. 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 left Pisa and all my students to earn my bread elsewhere and on a different arena than 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 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. London was inexpensive in those days.

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.

 

MARINE NATURAL PRODUCTS AND CORAL REEFS

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

I started a systematic search of marine organisms that were likely to entail novel natural products. I carried out work in marine institutions in Europe and overseas, mainly in the great network of the French oceanography. To secure samples of marine invertebrates and algae, I turned my leisure activity as a diver, during my youth in Livorno, into professional activity. A lively period in a team of young coworkers attracted to Trento from the universities of Naples, Bologna and Padua and skilled technicians. This work was more connected than before with daily life, and brought me to close relationships with the big research pharma.

My work is characterized by two features which had gone largely disregarded in the research on marine natural products, devoted to only unravel the structure and bioactivity of marine natural products on productive phyla: 

exploration of the productivity of neglected phyla, including marine ciliates, marine fungi, brachiopods, antipatharians and hexactinellid sponges. For the latter three phyla - which proved scarcely productive - I had support by French oceanographic organizations. For marine ciliates - where we brought to light the chemistry exploited by this fundamental phylum in the food chain - I looked for support by the group of marine biologists headed by professor Fernando Dini at the University of Pisa.  For marine fungi - where for the first time complex organic molecules were brought to light - I looked for support by the Ciba-Geigy headed by dr. Vincenzo Cuomo.

investigation of the chemical behavior of new natural products, which included                                                       --branched C15 lipids of Laurenica microcladia,

--chemical transformations clarifying the active sites in the antitumor activity of the alkalods agelastatins of Agelas dendromorpha

 --cis-trans photoisomerization, and thermal reversal, of alkaloids of dendrophylliids as a process to protect these surface corals from solar radiation

--unique reactivity of triplet dioxygen with singlet organic molecules of the sponge Raspailia plumila

--photochemical conversion of xenicane into crenulatane diterpenoids with the seaweed Dictyota sp. of Senegal

 

My field and lab marine studies were carried out at the

Stazione Zoologica di Ganzirri

Station Zoologique de Villefranche

INSERM 303 Villefranche-sur-Mer

Station Marine d'Endoume, Marseille

Laboratoire Arago, Banyuls-sur-Mer

Station Biologique de Roscoff

Station Biologique, Archachonne

Hawaii Institute of Marine Biology, Honolulu, Coconut Island

ORSTOM Centre de Noumea, Nouvelle Caledonie,

always enjoing a view on the sea from the window of my lab.

I also carried out field work along the south coast of Livorno and on the Elba Island

Field work involved collecting samples by diving and dredging. Lab work also involved culturing organisms in pioneering work on marine fungi in collaboration with Ciba-Geigy, and marine ciliates in collaboration with Fernando Dini, Professor of Biology at the University of Pisa.

It was in those years that 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.

 

ALESSANDRO BALLIO AND THE ACCADEMIA DEI LINCEI

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 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. I remember with nostalgia the enlightening discussions with Alessandro about my research while walking around the gardens of the Accademia. 

It was at the Lincei that I took a major writing, F. Pietra “Biodiversity and Natural Product Diversity” (Tetrahedron Organic Chemistry Series, Volume 21); Elsevier, Oxford 2002 Dedicated to Alessandro Ballio "Who made this work possible", 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. It is still sold, after two decades.

 

LECTURES

I delivered named lectures at meetings, universities and pharma research centers. The ones I can remember had place at the

ETH Zuerich (invitation by Prof Heinrich Zollinger) 1965 "Isotope effects in the nucleophilic reactions of protic amines with nitro-activated substrates".

La Sapienza Universita' di Roma (invitation by Prof Gabriello Illuminati) 1965 "Meccanismi di reazione di sostituzione nucleofila aromatica.

Universita' di Bari (invitation by Prof E. Todesco) 1970 "Chimica di troponoidi".

University of Dundee (invitation by Prof R. Foster) 1974.

Strathclyde University Glasgow ( invitation byProf P.L. Pauson) 1974.

Durham University (invitation by Dr M. Crampton) 1974.

University of Liverpool (invitation by Prof C.W. Rees) 1974.

UNESCO European Intensive Course, Banyuls-sur-Mer, August-September 1982.

CNRS Gif-sur-Yvette (invitation by 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 (invitation by Prof A. Meinesz) 1991.

Seventh International Symposium on Marine Natural Products, Capri (invitation by Prof L. Minale) 1992. 

La Sapienza Universita' Roma (invitation by 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 (invitation by 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" (invitation by Dr Vittorio Farina)

Universita' di Siena (invitation by 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". invitation by Prof Cardellina.

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 Between 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".

 

AS A REVIEWER AND SUPERVISOR

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.

FINANCIAL SUPPORT

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.

 

AS A FICTION WRITER 

 My short novel “The old man and the roading dog”, which appeared on the Gray's Sporting Journal Augusta, Georgia, 2005, 30, 1316, represents an insight into the psychology of the pointing dog and his prey. At that time I had to decide whether taking this new avenue - which had good prospects of revenues - or continuing with research in biochemistry, where I often had to pay for equipment from my pocket. I decide for the latter but I still wonder what the other avenue would have brought to me. I could have not do both.

 

THE ACCADEMIA LUCCHESE DI SCIENZE, LETTERE E ARTI and MY LAST PROJECT

I retired from the university before the terms, disappointed to my failure to convince the faculty to establish a full degree in Biochemistry. Unique among developed (and also many emerging countries) countries, the Italian university still does not offer such a fundamental degree, from which came such techniques as the PCR, which has revolutionized molecular biology. 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. I was also disappointed that the one of my coworkes who did the most  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 of isocolchicine, absent from 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. This constitutes a new mechanism 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; https://doi.org/10.1002/adts.201900253

Along my long-term interest in antitumoral agents, a special place is occupied by the sarcodictyins, antitumor agents from a Mediterranean coral, which 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 last project is in continuation of my interest in antitumor agent. It concerns the agelastatins, new skeleton alkaloids that we isolated by deep-water dredging from a sponge of the South Seas several years ago - at the time I was frequently engaged with French ovceanographic institutions -  and which revealed potent antitumor activity (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 DOI:10.1039/C39930001305

The bioactivity of agelastatin A was later ascribed to the inhibition of trascription, by being hosted at the A site of the PCT of the ribosome (McClary et al 2017, DOI: 10.1016/j.chembiol.2017.04.006) and it has been 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).

I am  now trying to understand by computer simulation what is still elusive to experimental investigation about the behavior of the agelastatins, which could help bringing these alkaloids to clinical use. 

 

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INSPIRATIONAL THOUGHTS

March 13, 2020

 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.