Paolo Vezzoni

Consiglio Nazionale delle Ricerche (CNR), Istituto di Ricerca Genetica e Biomedica (IRGB), Faculty Member

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Paolo Vezzoni, nato a Milano il 14.11.1950, si è laureato in Medicina e Chirurgia nel 1974 presso l’Università degli Studi di Milano. Ha conseguito la specialità di Endocrinologia nel 1977 e di Oncologia nel 1980. Dopo un periodo trascorso presso l’Istituto Nazionale dei Tumori di Milano, dal 1987 in poi ha lavorato al CNR di Milano, dove si è occupato di genetica umana nell’ambito del Progetto Genoma diretto dal prof Renato Dulbecco, di cui è stato vicecoordinatore. In qualità di Dirigente di Ricerca presso l’Istituto di Ricerca Genetica e Biomedica (IRGB) ha coordinato il Laboratorio di Biotecnologie Mediche del CNR presso l’Istituto Clinico Humanitas.
E’ autore di oltre duecento pubblicazioni scientifiche e di quattro libri. Il più rilevante è: “Intersezioni. Questioni biologiche di rilevanza filosofica”, McGrawHill, 2000. Altri libri: “Biotecnologie della vita quotidiana”, Laterza, 2000 (con A. Bazzi, vincitore del 1° premio Serono per la divulgazione scientifica, 2003); “Si può clonare un essere umano”, Laterza, 2003; e “Il futuro e il passato dell’uomo”, Bruno Mondadori, 2006. Per l’Enciclopedia Treccani ha curato la voce “Biotecnologie” e “Chimerismo”. Per la rivista “Le Scienze” ha scritto vari articoli e curato insieme a Dulbecco il dossier “Il Progetto Genoma Umano” (Quaderno n. 100 D, 1998) e un inserto su “Clonazione: problemi etici e prospettive scientifiche” (Le Scienze, suppl, maggio 1997).
L'ultima sua opera, "Minima Christiana", riprende quanto iniziato in "Intersezioni", discutendo ulteriormente temi filosofici e scientifici fondamentali per la comprensione della natura umana, ponendo dei limiti a quanto la religione cristiana può predicare al lume della ragione.
Address: Milan, Lombardy, Italy

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Single-cell analysis of ploidy and centrosomes underscores the peculiarity of normal hepatocytes Curriculum di Genomics, Proteomics e tecnologie correlate

The literature reports that, contrary to most other cell types, adult hepatocytes are polyploid c... more The literature reports that, contrary to most other cell types, adult hepatocytes are polyploid cells with a DNA content of 4, 8 or even 16 haploid genomes. In fetal and early neonatal life, hepatocytes are mononucleated diploid cells that, quite abruptly, become binucleated and polyploid soon after weaning. The generation of tetraploid intermediates is not an uncommon event in the liver. These cells have the potential to generate aneuploid progeny in the subsequent cell division, because of the presence of four centrosomes. Normally in diploid cells, at the beginning of mitosis, a single centrosome duplicates and the mother and daughter organelles migrate to opposite cell poles, directing the formation of the spindle, to guarantee a balanced chromosomal segregation. Four centrosomes can cluster together, mimicking a bipolar spindle, or, as reported for tumoral cells, act as single entities that generate multipolar spindle. The result of a multipolar division is a progeny with an unbalanced DNA content, differing in 1 or a few chromosomes. The formation of aneuploid progeny in hepatocytes has never been supported by experimental evidence for two reasons: 1) the classical approaches chosen to assess the hepatocyte ploidy lack the sensitivity to detect the small differences in DNA content that result from unbalanced chromosomal segregation; in addition, a quantitative and behavioural analysis of centrosomes in normal liver cells has not been thoroughly investigated; thus the presence of extranumerary centrosomes (i.e.,more than four) has never been postulated 2) The detrimental effects commonly attributed to aneuploidy made difficult to only hypothesize that a highly regenerative tissue such as the liver can contain aneuploid cells. It is thus of interest to note that some tissues are naturally aneuploid, like the embryonic brain, and in these tissues chromosome instability confers advantages properties to the cells. The main goal of my present work is to determine whether aneuploidy is a common feature of hepatocytes in physiological conditions. To address this goal I performed a quantitative analysis of the DNA content in normal hepatocytes during liver development and adulthood (at 18.5 post coitum, at 15 days, 1.5 RESULTS: I have demonstrated that aneuploidy and unbalanced DNA content in binucleated hepatocytes are common features of the normal adult liver. Despite the common belief that hepatocytes contain 1, 2 or no more than 4 centrosomes, our double staining for centrosome associated proteins reveals extranumerary centrosomes in a high percentage of cells as early as 15 days of age. I showed that in mice the period between 15 days and 1.5 months marks the transition from a liver with a prevalence of mononucleated cells to a liver with up to 75% of binucleated cells. My data demonstrate that this timing correlates with a switch of

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Chromosome Transplantation: Opportunities and Limitations

This article is an open access article distributed under the terms and conditions of the Creative... more

Aspectos científicos y éticos del Proyecto Genoma Humano en Italia

Equivoci e illusioni su identitŕ e modernizzazione

Sociologia e ricerca sociale, Oct 1, 2012

The theme of identity as a source of representations of self and social relations is at the cente... more The theme of identity as a source of representations of self and social relations is at the center of the contemporary sociological debate on dilemmas of modernization and has often been considered as the analytical framework within which such unresolved issues could be caught in their most emblematic profiling. Some of these controversial issues will be taken into account in the present essay through a comparison between the social sciences and the biomolecular sciences perspectives, both increasingly involved in the clarification of the most common misconceptions regarding the immutability of this set of signs and its progressive dissolution.

Adenocarcinoma of the Large Intestine in Young Adults

Tumori Journal, Nov 1, 1977

Twenty-eight cases of adenocarcinoma of the large intestine in patients under 30 years of age, ad... more Twenty-eight cases of adenocarcinoma of the large intestine in patients under 30 years of age, admitted to the National Cancer Institute of Milan from 1955 to 1975, are reported. Fourteen patients underwent radical surgery: of these, 8 are alive, and the survival times range from 8 months to 17 years. The 14 patients who received palliative therapy only aU died within 15 months. The degree of infiltration of the intestinal wall seemed to be the most significant prognostic factor. The worse prognosis for the neoplasia in young adults with respect to older people, already reported in the literature and confirmed by our data, seems to be correlated, more than with the histologic type or biologic behavior of the tumor, with the diagnostic delay, which results in more advanced forms, with respect to those seen in older patients, being observed at clinical examination. Although adenocarcinoma of the large intestine is prevalently found in older patients, numerous cases have been described in patients under 30 years of age (4, 8, 10, 12-20, 22). Of 17,875 deaths due to neoplasias of the colon and rectum recorded in Italy in 1966 and 1967, 187 (about 1 %) were in patients under 30 years of age (21). The frequency of adenocarcinoma of the large intestine in younger adults reported in the literature varies from 0.86 % (16) to 2.1 % (3) for patients under 30 years of age; from 0.45 % (17) to 1.1 % (22) for those under 20 to 25 years of age; and from 1.85 % (19) to 6.9 % (9) for those under 35 to 40 years of age. Here we report the case material of adenocarcinoma of the large intestine of the Istituto Nazionale Tumori of Milan from 1955 to 1975. On the basis of this data, compared and discussed in relation to those reported in the literature, we have attempted to determine the reason for the particularly severe prognosis that is usually associated with these neoplasias in young adults. CASE MATERIAL The case material consisted of 28 patients admitted to the Istituto Nazionale Tumori of Milan from 1955 to 1975 with a diagnosis of adenocarcinoma of the large intestine (table 1). Eight of the patients had previously undergone treatment Acknowledgments: The authors thank Ms. B. Johnston for preparation of the manuscript.

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Anti-CD3ε mAb improves thymic architecture and prevents autoimmune manifestations in a mouse model of Omenn syndrome: therapeutic implications

Blood, Aug 2, 2012

Omenn syndrome (OS) is an atypical primary immunodeficiency characterized by severe autoimmunity ... more Omenn syndrome (OS) is an atypical primary immunodeficiency characterized by severe autoimmunity because of activated T cells infiltrating target organs. The impaired recombinase activity in OS severely affects expression of the pre-T-cell receptor complex in immature thymocytes, which is crucial for an efficient development of the thymic epithelial component. Anti-CD3 monoclonal antibody (mAb) treatment in RAG2 ؊/؊ mice was previously shown to mimic pre-TCR signaling promoting thymic expansion. Here we show the effect of anti-CD3 mAb administration in the RAG2 R229Q mouse model, which closely recapitulates human OS. These animals, in spite of the inability to induce the autoimmune regulator, displayed a significant amelioration in thymic epithelial compartment and an important reduction of peripheral T-cell activation and tissue infiltration. Furthermore, by injecting a high number of RAG2 R229Q progenitors into RAG2 ؊/؊ animals previously conditioned with anti-CD3 mAb, we detected autoimmune regulator expression together with the absence of peripheral immunopathology. These observations indicate that improving epithelial thymic function might ameliorate the detrimental behavior of the cell-autonomous RAG defect. Our data provide important therapeutic proof of concept for future clinical applications of anti-CD3 mAb treatment in severe combined immunodeficiency forms characterized by poor thymus function and autoimmunity. (Blood.

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3073 – PBX1 Genetic Ablation Inhibits Tumor Growth in a Mouse Model of Myeloproliferative Neoplasm

Experimental Hematology, Aug 1, 2020

Pre B cell leukemia homeobox 1 (Pbx1) regulates the balance between self-renewal and differentiat... more Pre B cell leukemia homeobox 1 (Pbx1) regulates the balance between self-renewal and differentiation of hematopoietic stem cells, and maintains proto-oncogenic transcriptional pathways implicated in several tumors. Its aberrant expression was found in a subset of myeloproliferative neoplasms (MPN) patients bearing the JAK2V617F mutation. To investigate if Pbx1 contributes to MPN, and to explore its potential as therapeutic target, we generated a new mouse strain, that we called JP, by crossing a known JAK2V617F inducible knock-in MPN model with a Pbx1 conditional-ko. In JP mice we can simultaneously activate the human JAK2 mutation and delete Pbx1. Typical MPN features, such as thrombocytemia and granulocytosis, did not develop in the absence of Pbx1. Erythrocytosis, initially displayed by JP mice, gradually resolved over time. Moreover, splenic myeloid metaplasia and in vitro cytokine independent growth were rescued by Pbx1 inactivation. Through RNA-Sequencing we analyzed molecular pathways downstream of Pbx1 and involved in MPN maintenance in stem and progenitor cells. The aberrant transcriptome in the MPN model compared to wild-type was rescued by the absence of Pbx1. Our results demonstrate that inhibition of the Pbx1-driven transcriptional program is beneficial in MPN. Modulation of Pbx1 activity by direct targeting or by targeting its downstream mediators might thus represent a novel therapeutic approach.

Valutazione clinica ed auxolcgica in pazienti con diagnosi molecolare di diabete insipido nefrogenico ad ereditarietà legata al cromosoma X

Rivista Italiana di Pediatria, 2000

Generation of 3 clones of induced pluripotent stem cells (iPSCs) from a patient affected by Autosomal Recessive Osteopetrosis due to mutations in TCIRG1 gene

Stem Cell Research, 2020

Autosomal recessive osteopetrosis (ARO) is a rare inherited disorder leading to increased bone de... more Autosomal recessive osteopetrosis (ARO) is a rare inherited disorder leading to increased bone density with impairment in bone resorption. Among the genes responsible for ARO, the TCIRG1 gene, coding for the a3 subunit of the osteoclast proton pump, is mutated in more than 50% of the cases, increasing the importance of TCIRG1-iPSCs as disease model. We generated 3 iPSC clones derived from Peripheral Blood Mononuclear Cells (PBMCs) of a patient carrying the heterozygous mutations p.Y512X and c.2236 + 1G > A. A Sendai virus-based vector was used and the iPSCs were characterized for genetic identity to parental cells, genomic integrity, pluripotency, and differentiation ability.

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Molecular strategies in genetic diagnosis of transthyretin‐related hereditary amyloidosis

The FASEB Journal, Jul 1, 1992

Transthyretin-related hereditary (TTR) amyloidoses represent a clinically heterogeneous group of ... more

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Gene expression profiles of epithelial cells microscopically isolated from a breast-invasive ductal carcinoma and a nodal metastasis

Proceedings of the National Academy of Sciences of the United States of America, Dec 17, 2004

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X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations

Nature Genetics, Apr 9, 2006

Cornelia de Lange syndrome is a multisystem developmental disorder characterized by facial dysmor... more Cornelia de Lange syndrome is a multisystem developmental disorder characterized by facial dysmorphisms, upper limb abnormalities, growth delay and cognitive retardation. Mutations in the NIPBL gene, a component of the cohesin complex, account for approximately half of the affected individuals. We report here that mutations in SMC1L1 (also known as SMC1), which encodes a different subunit of the cohesin complex, are responsible for CdLS in three male members of an affected family and in one sporadic case. Cornelia de Lange Syndrome (CdLS, MIM 122470) is a clinically heterogeneous developmental disorder characterized by malformations affecting multiple systems. Although classical severe cases of CdLS are easily identified clinically, mild phenotypes are also frequent. Recently, the gene responsible for about half of CdLS cases was identified by two groups 1,2. This gene, NIPBL (homologous to Scc2 in yeast), codes for a protein that is implicated in chromosome cohesion. The core of the cohesin complex, first identified as responsible for chromatid cohesion, includes a heterodimer composed of SMC1 and SMC3, encoded by two members of the 'structural maintenance of chromosomes' gene family, and two non-SMC subunits, Scc1 (in humans, hSCC1 or hRAD21) and Scc3 (in humans, SA1 and SA2). Recent work suggests that these molecules assemble in a tripartite ring-shaped structure that interacts with DNA chains 3. In particular, in this recently proposed model, the two SMC subunits assume a rod-shaped conformation self-folded by antiparallel coiled-coil interaction and associate with each other through a 'hinge' domain positioned at one end of the rod, resulting in a V-shaped dimer. At the opposite end, each SMC molecule has a 'head' domain, whose engagement could 'close' or 'open' the ring: this region is also the site of interaction with Scc1 and Scc3 (ref. 4). However, at least three other

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Riprogrammare cellule umane

Le Scienze, 2008

Establishment and characterization of new mammary adenocarcinoma cell lines derived from double transgenic mice expressing GFP and neu oncogene

Cell Proliferation, Dec 1, 2006

A new murine cell line, named GFPneu, was established from a mammary adenocarcinoma arising in do... more A new murine cell line, named GFPneu, was established from a mammary adenocarcinoma arising in double transgenic MMTVneu × CMV-GFP mice. Breast tumours develop in 100% of females after 2 months latency, as a result of the overexpression of the activated rat neu oncogene in the mammary glands. All tissues, and in particular the breast tumours, express the GFP protein. This cell line was tumorigenic when inoculated into nude mice and the derived tumours showed the same histological features as the primaries from which they were isolated. Their histopathology reproduces many characteristics of human breast adenocarcinomas, in particular their ability to metastasize. The GFP marker allows us to visualize the presence of lung metastases in fresh tissues immediately, to confirm the histopathology. From a lung metastatic fluorescent nodule, we derived a further cell line, named MTP-GFP, which we also characterized. These two cell lines could be useful to study the role played by the neu oncogene in the maintenance of the transformed phenotype, in the metastatic process, to test novel therapeutic strategies to inhibit primary tumour growth and to observe the generation of distant metastases.

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The contribution of molecular biology in the diagnosis of human lymphomas

PubMed, 1986

The relationship between T cell receptor (TCR) beta and gene immunoglobulin heavy chain locus was... more The relationship between T cell receptor (TCR) beta and gene immunoglobulin heavy chain locus was investigated in 25 cases of unselected human lymphomas as well as in normal and non-neoplastic lymphoid tissues. Hybridizing our blots with Jurkat 2, a clone specific for the beta chain gene of TCR, did not demonstrate extra bands in non-neoplastic tissues composed of 50-95% T-cells. On the contrary, rearranged bands were detected in six out of six cases of T-cell lymphomas. No TCR beta gene rearrangements were detected in 11 B-cell lymphomas, which in turn presented modification of the immunoglobulin heavy chain gene germline configuration. Our results suggest that TCR beta chain gene rearrangements are a good marker for human T-cell neoplasias in humans and complement the analysis with immunoglobulin genes probes. Eighth samples were devoid of any rearrangements: this group comprises cases of Hodgkin's disease T-lymphoblastic lymphomas in clinical remission and malignancies of unknown origin, as discussed in the text. We conclude that the analysis using DNA probes specific for TCR beta and IgH genes can be of aid to the pathologist in the diagnosis and classification of human lymphomas.

Chromosomes, genes, and cancer breakpoints

Cancer genetics and cytogenetics, Dec 1, 2002

Estrogen Receptors and MPA Treatment in Metastatic Renal Carcinoma. A Preliminary Report

Tumori Journal, Dec 1, 1980

Ten previously untreated patients with metastatic renal carcinoma underwent transperitoneal radic... more Ten previously untreated patients with metastatic renal carcinoma underwent transperitoneal radical nephrectomy followed by high dosage MPA treatment. Estrogen receptors were determined in the specimen of all cases by the dextran-coated charcoal method: both the neoplastic tissue and the healthy parenchyma were tested. The disease progressed in 8 cases, and 2 patients are alive without any evidence of progressive disease 12 and 27 months after the operation. Very low receptor levels were detected in these 2 cases and one of them could be defined as borderline with our threshold criterion. However, receptors were undetectable in the neoplastic tissue from 4 of 8 patients who progressed. These questionable results justified the start of a prospective multicentric trial to study in a large number of cases both hormone receptors and clinical response to hormone therapy in human renal cancer.

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Cell fusion in the liver, revisited

World Journal of Hepatology, Feb 27, 2018

There is wide agreement that cell fusion is a physiological process in cells in mammalian bone, m... more There is wide agreement that cell fusion is a physiological process in cells in mammalian bone, muscle and placenta. In other organs, such as the cerebellum, cell fusion is controversial. The liver contains a considerable number of polyploid cells: They are commonly believed to originate by genome endoreplication, although the contribution of cell fusion to polyploidization has not been excluded. Here, we address the topic of cell fusion in the liver from a historical point of view. We discuss experimental evidence clearly supporting the hypothesis that cell fusion occurs in the liver, specifically when bone marrow cells were injected into mice and shown to rescue genetic hepatic degenerative defects. Those experiments-carried out in the latter half of the last century-were initially interpreted to show "transdifferentiation", but are now believed to demonstrate fusion between donor macrophages and host hepatocytes, raising the possibility that physiologically polyploid cells, such as hepatocytes, could originate, at least partially, through homotypic cell fusion. In support of the homotypic cell fusion hypothesis, we present new data generated using a chimera-based model, a much simpler model than those previously used. Cell fusion as a road to polyploidization in the liver has not been extensively investigated, and its contribution to a variety of conditions, such as viral

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Recapitulation of the Roberts syndrome cellular phenotype by inhibition of INCENP, ZWINT-1 and ZW10 genes

Gene, Apr 1, 2004

Roberts syndrome is an autosomal recessive disorder characterised primarily by symmetric reductio... more Roberts syndrome is an autosomal recessive disorder characterised primarily by symmetric reduction of all limbs and growth retardation. Patients have been reported to have premature separation of heterochromatin regions of many chromosomes and abnormalities in cell cycle. Given the rarity of the syndrome, the linkage analysis approach is not suitable to identify the responsible gene. In this work, a cell line derived from a patient affected by Roberts syndrome was characterized by cell biology and molecular cytogenetics, including comparative genomic hybridization and spectral karyotype. No recurrent chromosomal rearrangements were identified. Thereafter, based on the fact that premature chromatide separation is a reliable marker of the disease, we used antisense oligonucleotide technologies to inhibit six genes involved in various steps of the correct chromosome segregation, such as chromosome cohesion, kinetochore assembling, spindle checkpoint and spindle formation. We found that the inhibition of INCENP, ZWINT-1, ZW10 genes results in the appearance of mitotic cells characterised by centromere separation, chromosome aneuploidy and micronuclei formation. In addition, INCENP, ZWINT-1, ZW10 antisense-treated chromosome morphology was very similar to that of Roberts chromosome when analysed by atomic force microscopy. We concluded that INCENP, ZWINT-1, ZW10 gene inhibition results in cellular phenocopies of Roberts syndrome. Taken together, these findings support a possible role of these genes in the pathogenesis of Roberts syndrome.

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Fetal Liver Cells Transplanted in Utero Rescue the Osteopetrotic Phenotype in the oc/oc Mouse

American Journal of Pathology, Mar 1, 2009

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Paolo Vezzoni

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