How Disregard For Science in Lucca May Promote Human Cancer

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The illustration at top left illustrates my success in completing the structure of the acid-sensing ion channel cASIC1a, which is involved in ischaemic neuronal injury (F. Pietra, Chemistry&Biodiversity, 2015, 12, 350-357). Inhibiting this channel may relieve from pain upstream of opiate systems, which may turn to be particularly useful in Lucca old town in a near future, when the young residents will have accumulated enough carcinogens from the oily aerosol, which, according to the scientific literature, is emitted by restaurant chimneys. The one at the top right is not from a Brazilian favela, rather from Lucca old town, emerging from a recently installed restaurant at the ground floor. This chimney, as a striking example of modern architecture, faces the side of the 1200-Gothic San Pietro in Somaldi and emits the typical stench of roasted meat and fish, which penetrates into the flats from the windows. According to science, that stench is slowly released from the oily aerosol that spreads down, signaling the carcinogenic and mutagenic compounds dissolved in the oil. The idea that an oily aerosol does not sense gravity is like the idea of demonstrating that Earth is flat by the rocket man.

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This page describes both my academic activity (as from the illustration at top left) and my battle against exploitation of residents in Lucca old town in favor of health-threatening commercial activities (as from the picture at top right).

Let me first tell you about my battle against exploitation of the residents. According to the scientific literature, the oily aerosol from commercial high-temperature cooking of meat and fish, as well as frying with polyunsaturated oils, spreads down from the exhaust, unlike gaseous emissions from heating devices. The result is conveying mutagenic and carcinogenic compounds into the lungs of residents, chiefly through the underlying windows. The most powerful such compounds are benzo[a]pyrene, E-2,4-decadienal and 2-amino-1-methyl-6-phenylimidazo[4,5,-b]pyridine.These compounds are known to accumulate into the human body, regardless of the small concentration they might have in the aerosol. Most affected are the youngest residents, as they offer time enough for the accumulation of these compounds at risky levels. At any level, particularly affected are individuals with inherited heterozygous BRCA2 mutations or defective production of glutathione-S-transferase. According to the scientific literature, the odorous compounds are released slowly from the oily droplets, thus revealing the presence of the carcinogenic compounds. In the most advanced countries, notably in Australia's NSW, but also in northern Europe, such emissions are prevented by the installation of very expensive filtering systems. Safety tests, in the form of odor assessments performed by a competent consultant, are carried out at the installation and thereafter regularly from time to time.From the typical odor from frying and heating meat or fish at high temperature, no such filtering systems are in use, or they are not maintained, in Lucca old town restaurants. In Lucca it is the health of the residents that contributes to the economical budget of the restaurants. Which are so densely distributed in the old town as it never occurred in the western world, thus their contribution of oily aerosol must be summed up in a old town sheltered by walls that prevent ventilation.

 

Let me now tell you about my scientific life. Live in my memory is the High School, where I learned how to set a scientific project from the Latin scholar Vincenzo Courier, how to simplify it from the great mathematician Emilio Ceccarelli, and how to run a scientific institution from the Dean, the German scholar Achille Radaelli.From the university, it were only the lectures in electrochemistry by Antonio Foffani that gave me a way. Appointed as an assistant at the university, it happened that I purchased the first edition of "Basic Principles of Organic Chemistry" by Roberts & Caserio. This was a breakthrough in my scientific career, this book opening my mind to modern organic chemistry.Shortly later, while getting the degree of Libero Docente, I also got a grant by CNR for a study leave at the Imperial College in London, under Derek Barton. This opened my eyes to the big organic chemistry.

 

In the meantime I had launched a program of studies in physical organic chemistry, exemplified by

G. Biggi, F. Del Cima and F. Pietra "Nucleophilic substitution with rearrangement on troponoids. The reaction of 2-(1-azoniabicyclo[2,2,2] oct-1-y1[3,5,7-2H3])cyclohepta-2,4,6-trien-1-one iodide with piperidine leading to 2-piperidino[4,6-2H2]cyclohepta-2,4,6-trien-1-one via 7,2 addition-elimination." Journal of the American Chemical Society, 1972, 94, 4700-4707. For this activity I performed as Invited Lecturer of the British Council for the year 1974 throughout Scotland and northern England.

 

 With my appointment to the Chair of Organic Chemistry by the University of Trento, I was given resources enough to start work on marine natural products. I turned my leisure activity as a diver into professional activity by marine stations throughout the world. Two lines of these studies are most relevant to human welfare. One concerns the sarcodictyins (M. D'Ambrosio, A. Guerriero, and F. Pietra "Sarcodictyin-A and sarcodictyin-B, novel diterpenoidic alcohols esterified by N(1)-methyl-(E)-urocanic acid. Isolation from the Mediterranean stolonifer Sarcodictyon roseum" Helvetica Chimica Acta, 1987, 70, 2019-2027), that led to the US Patent 5,869,514 with Pharmacia & Upjohn on these potent antitumor agents with Taxol-like activity, but also active on cancer lines that are resistant to Taxol. In view of recent experiments that show that Taxol acts by misregulating chromosome segregation, rather than by mitotic arrest, as was previously thought (B.A. Weaver, Sci Transl Med. 2014 March 26; 6(229): 229ra43. doi:10.1126/scitranslmed.3007965), it would be  interesting to carry out similar tests with the sarcodictyins. The problem is the availability. The stolonifer is relatively rare and culture of the entire coral or cells have never been attempted, as far as I know. On the other hand, the SCRIPPS total synthesis of sarcodictyin A ( J. Am. Chem. Soc., 1998, 120, 8661–8673) is too complex and of too low yield to be of industrial interest. Thus, although Taxol needs to be replaced because of its damage of the long axons, while the scientific community, baffled from the difficulties, has largely abandoned the art of the total synthesis, the sarcodictyins are destined to remain as a golden piece in the literature rather than a weapon in the pharmacy against malignancies. However, the Chinese have taken the challenge of total synthesis and it is my aim now to stimulate them tho attack the sarcodictyins by showing them how they behave within tubulin. This is my task now through computer simulations.

The other line  concerns other antitumor agents, the agelastatins (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) which have now been patented by the Mayo Foundation For Medical Education And Research, Osaka University, against brain tumors (Treating brain cancer using agelastatin a (aa) and analogues thereof, PCT/US2013/064605, Apr 17, 2014). The agelastatins, although found in a relatively rare marine sponge, are amenable to industrial-type total synthesis, which paved the way to clinical trials.Interestingly, Michele D'Ambrosio (the only former coworker with whom I saved relationships) has visited me in July 17 at the Accademia,  stimulating me to continue with experimental chemistry of agelastatins.

 
 

To this period belongs a review paper that served to unify concepts about the terrestrial and the marine worldsF. Pietra "Structurally similar natural products in phylogenetically distant marine organisms, and a comparison with terrestrial species" Chemical Society Reviews 1995, 24, 65-71.

 

For these studies I was awarded the Maria Teresa Messori Roncaglia ed Eugenio Mari Chemistry Prize by the Accademia Nazionale dei Lincei, 1998, and I was appointed to the Centro Linceo Beniamino Segre, at the Accademia Nazionale dei Lincei.

 

During the Lincei period in Rome I was engaged in a major writing, F. Pietra “Biodiversity and Natural Product Diversity” (Tetrahedron Organic Chemistry Series, Volume 21); Elsevier, Oxford 2002. This book offered a new perspective on natural products, no more from only the chemical or biogenetic point of views, but linking them to taxonomy and genetics as well.

 

I delivered named lectures at universities, symposiums, and the pharmaceutical industry throughout the world, including the Gordon Conferences. I represented Italy for the chemistry of biologically active natural products at the Marconi Symposium in Sydney and Melbourne in the year 1995. I also acted as a referee for the appointment to chairs and the evaluation of PhD theses for Australia, France, New Caledonia and India. In contrast, during my long career as a full professor, I was never asked to act as a referee for promotions at universities in my country.

 

I 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, while perhaps three hundred blue-dressed beautiful girls were congratulating the new doctor in science. 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.


 

I also offer advice as a member of the editorial board of scientific journals.

 

 I retired from the university before the terms, disappointed by my failure to convince the Faculty in Trento to found a full degree in Biochemistry. Unique among developed (and emerging) countries, the Italian university still does not offer such a fundamental degree. Then, I moved to theoretical studies, mainly on proteins and their interaction with the small molecule. An example is the unraveling of what was still hidden about the structure of the ASIC1a channel, as in the illustration at the top of this page.

 

Financial support to my research at the university came  from both public (MPI, CNR, EU European Projects) and private funding (Pharmacia&Upjohn, IRST), while the university itself provided rooms, water and electricity. Thereafter, during the Accademia Lucchese period, my research has been  financially supported by public funding (CINECA-ISCRA), to provide access to mainframes like the Blue-Gene and the IBM NextScale.

 

From my activity as a fiction writer:

F. Pietra “The old man and the roading dog” Gray's Sporting Journal (Augusta, Georgia, the leading sporting journal in the US) 2005, 30, 1316. It represents an insight into the psychology of the pointing dog and his prey.