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Centro Europeo di Risonanze Magnetiche una infrastruttura di ricerca nel Polo Scientifico dell’Università di Firenze. Claudio Luchinat CERM Università di Firenze. Il Polo Scientifico di Sesto Fiorentino. The Magnetic Resonance Center in Florence. 700b. Bio-labs. 800. 950. 850ss. 900.

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Claudio Luchinat CERM Università di Firenze

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Claudio luchinat cerm universit di firenze

Centro Europeo di Risonanze Magnetiche

una infrastruttura di ricerca nel Polo Scientifico dell’Università di Firenze

Claudio Luchinat

CERM

Università di Firenze


Claudio luchinat cerm universit di firenze

Il Polo Scientifico di Sesto Fiorentino


Claudio luchinat cerm universit di firenze

The Magnetic Resonance Center in Florence

700b

Bio-labs

800

950

850ss

900

700

Conference room

Library

400

Workshop

500

Computer room

600

600b

700ss

Department

of Chemistry

(offices, bio-labs,

relaxometer, instruments..)

GENEXPRESS, CRYST, CISM

DaVEB Biobank


Claudio luchinat cerm universit di firenze

CERM instrumentation

700 MHz WB

NMRinstrumentation

Cryo

700 MHz (b)

Cryo

500 MHz

Cryo

800 MHz

Cryo

700 MHz (a)

Cryo

600 MHz

400 MHz

600 MHz

Cryo 950 MHz

850 MHz WB

Cryo 900 MHz


Claudio luchinat cerm universit di firenze

The Magnetic Resonance Center in Florence

Electron/nuclear relaxation (Relaxometry)

Drug discovery

Structural proteomics

Metabolomics

Protein structure determination

Methodological advancements in NMR

Solid state NMR

ICT and computational biology

700b

Bio-labs

800

950

850ss

900

700

Conference room

Library

400

Workshop

500

Computer room

600

600b

700ss

We provide access to European researchers since 1994

New access program Bio-NMR (2010-2014) started September 2010

Access provided by Florence, Frankfurt, Utrecht, Lyon/Grenoble, Berlin, Zurich, Brno, Ljubljana, Oxford, Birmingham, Goteborg

Department

of Chemistry

(offices, bio-labs,

relaxometer, instruments..)

GENEXPRESS, CRYST, CISM

DaVEB Biobank


Claudio luchinat cerm universit di firenze

Metabolomica:

uno sguardo molecolare sulla salute e sulle malattie

Claudio Luchinat

CERM

Università di Firenze


Claudio luchinat cerm universit di firenze

The Research Centers of FiorGen

CERM

Scientific Campus

Sesto Fiorentino

Biomedical Campus

Careggi


Claudio luchinat cerm universit di firenze

Scientific Publications

146 publications on high level journals, starting from 2004

Independent reviewers attested the high scientific level of the Foundation

“The scientific production of FiorGen is quite impressive”

Prof. Arturo Falaschi

Scuola Normale Superiore – Pisa

Distinguished Scientist ICGEB Trieste

Aprile 2008

“The scientific productivity of FiorGen is of excellent level”

Prof. Giuseppe Novelli

Tor Vergata University of Rome

University of Arkansas (USA)

WPQ PGx EMEA (UK)

Maggio 2008


Claudio luchinat cerm universit di firenze

What is Metabolomics?

Metabolomics is a further “omic” science that is now emerging with the purpose of “elaborating a comprehensive analysis of the metabolome, which is the complete set of metabolites in an organism or cell”.

Genomics tells you what could happen. Metabolomics tells you what has happened. Only a few thousand metabolites.

!! However, not negligible external variability !! (source of noise)


Claudio luchinat cerm universit di firenze

Examples of metabolites

O

O

O

H

O

H

H

O

S

u

c

c

i

n

i

c

a

c

i

d

O

O

O

P

y

r

u

v

i

c

a

c

i

d

O

H

H

O

O

O

O

x

a

l

o

a

c

e

t

i

c

a

c

i

d

Acetyl CoA


Claudio luchinat cerm universit di firenze

Metabolomics

Study of small molecules in biological fluids

+

Metabolic fingerprint


Claudio luchinat cerm universit di firenze

H

H

|

|

__

__

__

__

C

C

H

O

H

|

|

H

H

1H NMR spectrum of ethanol


Claudio luchinat cerm universit di firenze

1H NMR spectrum (upfield part) of human urine


Claudio luchinat cerm universit di firenze

1H NMR spectrum (downfield part)of human urine


Claudio luchinat cerm universit di firenze

2 Routes to Metabolomics

ppm

7

6

5

4

3

2

1

25

PC2

20

15

TMAO

creatinine

10

hippurate

allantoin

5

creatinine

taurine

citrate

0

urea

-5

hippurate

2-oxoglutarate

water

-10

succinate

fumarate

-15

-20

PC1

ppm

7

6

5

4

3

2

1

-25

-30

-20

-10

0

10

  • Two approaches:

  • Identify as many metabolites as possible

  • Use the whole spectrum as a fingerprint (statistics)

Chemometric methods

(fingerprinting and pattern recognition)

Quantitative

methods


Claudio luchinat cerm universit di firenze

The fingerprint

Traditional clinical analysis:

Metabolomics:

Few already known metabolites for some disease (e.g. glucose for diabetes, etc…)

All metabolites are analyzed together without prior knowledge


Claudio luchinat cerm universit di firenze

The fingerprint

What are they doing ?


Claudio luchinat cerm universit di firenze

The fingerprint

Only an analysis at a global level can tell the whole story


Claudio luchinat cerm universit di firenze

METabolomic REFerence

Ind 1

Ind 2


Claudio luchinat cerm universit di firenze

METabolomic REFerence

Ind 1

Ind 2


Claudio luchinat cerm universit di firenze

METabolomic REFerence

Convex hulls of 22 donors in the three most significant PCA-CA dimensions

PCA for data reduction

CA for obtain well separated clusters

KNN for classification

99% accuracy in montecarlo cross validation

“natural” gender discrimination

MALE

FEMALE

Assfalg, Bertini, Colangiuli, Luchinat, Schäfer, Schütz, Spraul, PNAS, 2008, 105, 1420-4


Claudio luchinat cerm universit di firenze

The signature of Our Body

  • There exists an individual human metabolic phenotype (metabotype)

  • The metabotype consists of a variable part (environment) and an invariant part (genetics + environment)

  • The invariant part persists for at least two-three years (if the diet is averaged using collection of multiple samples)

  • The discovery of the existence of individual metabotypes is the baseline for Biomedical Researches

Assfalg, Bertini, Colangiuli, Luchinat, Schäfer, Schütz, Spraul, PNAS, 2008

Bernini, P.; Bertini, I.; Luchinat, C.; Nepi, S.; Saccenti, E.; Schäfer, H.; Schütz, B.; Spraul, M.; Tenori, L. J. Prot. Res. 2009


Claudio luchinat cerm universit di firenze

Metabolomics @CERM/CIRMMP

  • Collaborative Projects

  • SPIDIA (7th framework program)

  • Standardization and improvement of pre-analytical procedures for in-vitro diagnostics.

  • CHANCE (7th framework program)

  • Evaluation of the impact of nutritional criticalities in population at risk of poverty using NMR metabolomics.

  • livSYSiPS (ErasysBio+)

  • The sistem biology of network stress based on data generated from in vitro differentiated hepatocytes derived from individual-specific human iPS cells.

  • ITFoM (FET Flagship Initiative)

  • The aim of ITFoM is to develop models of human pathways, tissues, and ultimately of the whole human, to create a “virtual patient” which will enable physicians to identify personalised prevention schedules and treatments adapted to each person.

  • Progetto COSMOS (EU Coordination action)

  • To develop new standard for metabolomics sutdies

  • Progetto BioMedBridges (EU Coordination action)

  • To develop a unified framework for biomedical studies in Europe

  • Progetto Melanoma (Ente Cassa di Risparmio di Firenze)

  • New strategies for diagnosis prognosis and treatment of melanoma.


Claudio luchinat cerm universit di firenze

Metabolomics @CERM/CIRMMP

  • Collaborations

  • Celiac Disease (Prof. Antonio Calabrò, Careggi Hospital)

  • Geriatric patients (Dr. Laura Biganzoli, Prato Hospital)

  • Diabetes in young (Dr. Sonia Toni, Mayer Children’s Hospital)

  • BPCO (Dr. Massimo Miniati, Careggi Hospital and CNR Pisa)

  • Metastatic Colorectal Cancer (Dr. Benny W. Jensen, Herlev Hospital, Copenhagen)

  • Periodonitis (Dr. Mario Aimetti, University of Turin)

  • Bladder and Prostate Cancer (Dr. Marco Carini, Careggi Hospital)

  • Cardiovascular Risk (Dr. Adriana Tognaccini, Pistoia Hospital and AVIS Toscana)

  • Intestinal Bowel Diseases (Prof. Maurizio Vecchi, University of Milan)

  • Heart Failure (Prof. Franco Gensini, University of Florence)

  • Breast Cancer (Dr. Angelo Di Leo, Prato Hospital)

  • Bariatric Surgery (Prof. Bernd Schultes, St. Gallen Hospital, Switzerland)

  • Metabolomics of the Mitochondrion (Prof. Roland Lill, University of Marburg, Germany)

  • Osteoarthritis (Prof. Brandi, University of Florence)

  • Krabbe disease (Dott.sa Alice Luddi, University of Siena)

  • Gestational diabetes (Dr. Dani, Careggi Hospital)


Claudio luchinat cerm universit di firenze

Celiac Disease Metabolomics

Clusterization of Celiac and Healthy subject serum spectra

Bertini, I.; Calabrò, A.; De Carli, V.; Luchinat, C.; Nepi, S.; Porfirio, B.; Renzi, D.; Saccenti, E.; Tenori, L. The metabonomic signature of celiac disease, J. Proteome Res. 2009,8(1), 170


Claudio luchinat cerm universit di firenze

Celiac Disease Metabolomics

Clusterization of Celiac and Healthy subject serum spectra

and corresponding Follow-up

Bertini, I.; Calabrò, A.; De Carli, V.; Luchinat, C.; Nepi, S.; Porfirio, B.; Renzi, D.; Saccenti, E.; Tenori, L. The metabonomic signature of celiac disease, J. Proteome Res. 2009,8(1), 170


Claudio luchinat cerm universit di firenze

Celiac disease

There exist a metabolic fingerprint of celiac disease

Celiac – Healthy Subjects – Cross: predicted Potential Celiac

These alteration are present also in potential celiac subjects: so they precede the intestinal damage

Potential CD largely shares the metabonomic signature of overt CD. Most metabolites found to be significantly different between control and CD subjects were also altered in potential CD. Our results suggest early institution of GFD in patients with potential CD

Bertini, I.; Calabrò, A.; De Carli, V.; Luchinat, C.; Nepi, S.; Porfirio, B.; Renzi, D.; Saccenti, E.; Tenori, L. The metabonomic signature of celiac disease,J. Proteome Res. 2009,8(1), 170

Bernini P, Bertini I, Calabrò A, la Marca G, Lami G, Luchinat C, Renzi D, Tenori L. Are patients with potential celiac disease really potential? The answer of metabonomics. J. Proteome Res. 2010


Claudio luchinat cerm universit di firenze

http://www.fiorgen.net/ https://www. davincieuropeanbiobank.org


Claudio luchinat cerm universit di firenze

Breast cancer metabolomics

Classification between Pre-Op and Metastatic subjects.

Accuracy ~80%

Other comparisons

NOESY

CPMG

Healthy vs

Met

Accuracy

72.67%

Healthy vs

Met

Accuracy

73.44%

Healthy vs

Post-op

Accuracy

70.00%

Healthy vs

Post-op

Accuracy

75.80%

Post-op vs

Met

Accuracy

70.00%

Post vs

Met

Accuracy

74.96%


Claudio luchinat cerm universit di firenze

ColorectalCancerMetabolomics

Serum samples from 139 HS and 155 patients with mCRC, included in a prospective phase II study of 3rd line treatment with cetuximab and irinotecan

We can discriminate healthy controls from mCRC with almost 100% accuracy.

We can predict the overall survival of the patients

Cross-validated results on the Training Set:

Sensitivity :79.9%

Specificity:76.4%

Accuracy:78.5%

Univariate Cox Regression Analysis for the Validation Set:

HR:3.30

95% CI:2.02 to 5.37

P:1.75 ∙ 10-6

PLS-CA model: long survival, in blue; short survival, in yellow

Bertini I, Cacciatore S, Jensen BV, Schou JV, Johansen JS, Kruhøffer M, Luchinat C, Nielsen DL, Turano P., Cancer Res. 2012 Jan 1;72(1):356-64. Epub 2011 Nov 11


Claudio luchinat cerm universit di firenze

Heart failure metabolomics

Classification between different subgroups of Heart failure patients (1D CPMG spectra).

Patients are separated from healthy, but there is not any significant difference between the disease grading that could reflect the clinical severity of the disease.

Although good discrimination between healthy and HF subjects with a severe disease, if not expected, was easy to be hypothesized, a comparable good discrimination ability between healthy and HF subjects with a mild disease was unexpected and appears rather counter-intuitive.


Claudio luchinat cerm universit di firenze

Metabolomics of Melanoma


Claudio luchinat cerm universit di firenze

Fingerprint of Obesity

Fingerprint of obesity

The prediction of OW (stars) using the NW (green) vs SO (blue)

model classify almost all OW as SO (except two)


Da vinci european biobank

Da Vinci European BioBank


Claudio luchinat cerm universit di firenze

FROM METABOLOMICS

Dalla Metabolomica

Analisi Metabolomica

Metabolomic analysis

Validation of

Controllo

Definition of

Definizione di

sample quality

Qualitàdi campioni

new SOPs

Nuove SOP

in biobanks

Nelle biobanche

TO BIOBANKS

Alle Biobanche

Metabolomica

L’approccio combinato di metabolomica (Prof. Claudio Luchinat) e biobanca (Prof. Paola Turano) ci rende unici in questo settore della scienza

Spettro NMR di urina di un donatore sano

http://www.fiorgen.net/ https://www. davincieuropeanbiobank.org


Claudio luchinat cerm universit di firenze

Fiorgen ha implementato una Biobanca su standard europei che è inserita nei programmi nazionali ed europei. Essa raccoglie campioni biologici (sangue, urine, biopsie) di molte malattie .

Collezioni di campioni della Biobanca:

Scompenso cardiaco (Prof. Gianfranco Gensini)

Melanoma (Prof. Nicola Pimpinelli)

Cancro alla mammella (Prof. Angelo Di Leo, e USA)

Cancro al colon (Prof. Benny V. Jensen, Danimarca)

Disturbi alla prostata (Prof. Marco Carini)

Celiachia (Prof. Antonio Calabrò)

Osteoporosi (Prof.ssa Maria Luisa Brandi)

http://www.fiorgen.net/ https://www. davincieuropeanbiobank.org


Claudio luchinat cerm universit di firenze

The Future of Medicine

Metabolomics can monitor the same individual in a multidimensional space

hepatocarcinoma

Colorectal cancer

cirrhosis

steatosis

Intestinal bowel disease

Metabolic syndrome

Healthy aging

Diabetes

Hypertension

Hearth Failure


Claudio luchinat cerm universit di firenze

Et interviene di questa come dicono e’ fisici dello etico, che nel principio del suo male è facile a curare e difficile a conoscere, ma, nel progresso del tempo, non l’avendo in principio conosciuta né medicata, diventa facile a conoscere e difficile a curare.

Machiavelli, Il Principe, cap. 3


Claudio luchinat cerm universit di firenze

Il sogno

Dotare ogni cittadino di un chip in cui sono riportati il genoma, il proteoma e il metaboloma al fine di monitorarne nel tempo lo stato di salute

http://www.fiorgen.net/ https://www. davincieuropeanbiobank.org


Claudio luchinat cerm universit di firenze

The Future of Medicine

From general to personalized medicine


Claudio luchinat cerm universit di firenze

Ivano Bertini

December 6, 1940

– July 7, 2012


Claudio luchinat cerm universit di firenze

Metabolomics @CERM/CIRMMP

  • Metabolomics Publications

  • Human phenotypes

  • Assfalg M, Bertini I, Colangiuli D, Luchinat C, Schäfer H, Schütz B, Spraul M. Evidence of different metabolic phenotypes in humans. Proc Natl Acad Sci U S A 2008;105(5):1420-4. (IF=9.771).

  • Bernini P, Bertini I, Luchinat C, Nepi S, Saccenti E, Schäfer H, Schütz B, Spraul M, Tenori L. Individual human phenotypes in metabolic space and time. J Proteome Res. 2009 Sep;8(9):4264-71. (IF=5.460).

  • Cardiovascular diseases

  • Bernini P, Bertini I, Luchinat C, Tenori L, Tognaccini A. The cardiovascular risk of healthy individuals studied by NMR metabonomics of plasma samples. J Proteome Res 2011. [Epub ahead of print] (IF=5.460).

  • Celiac disease

  • Bernini P, Bertini I, Calabrò A, la Marca G, Lami G, Luchinat C, Renzi D, Tenori L. Are patients with potential celiac disease really potential? The answer of metabonomics. J Proteome Res 2011 Feb 4;10(2):714-21. (IF=5.460).

  • Bertini I, Calabrò A, De Carli V, Luchinat C, Nepi S, Porfirio B, Renzi D, Saccenti E, Tenori L. The metabonomic signature of celiac disease. J Proteome Res. 2009 Jan;8(1):170-7. (IF=5.460).

  • Ozono terapy

  • Travagli V, Zanardi I, Bernini P, Nepi S, Tenori L, Bocci V. Effects of ozone blood treatment on the metabolite profile of human blood. Int J Toxicol 2010;29(2):165-74. (IF=1.762).


Claudio luchinat cerm universit di firenze

Metabolomics @CERM/CIRMMP

  • Breast cancer

  • Tenori L, Oakman C, Claudino WM, Bernini P, Cappadona S, Nepi S, Biganzoli L, Arbushites MC, Luchinat C, Bertini I, Di Leo A. Exploration of serum metabolomic profiles and outcomes in women with metastatic breast cancer: A pilot study. Mol Oncol. 2012 Jun 1. (IF=4.250).

  • Oakman C, Tenori L, Claudino WM, Cappadona S, Nepi S, Battaglia A, Bernini P, Zafarana E, Saccenti E, Fornier M, Morris PG, Biganzoli L, Luchinat C, Bertini I, Di Leo A. Identification of a serum-detectable metabolomic fingerprint potentially correlated with the presence of micrometastatic disease in early breast cancer patients at varying risks of disease relapse by traditional prognostic methods. Ann Oncol 2011 Jun;22(6):1295-301. (IF=6.452).

  • Oakman C, Tenori L, Biganzoli L, Santarpia L, Cappadona S, Luchinat C, Di Leo A. Uncovering the metabolomic fingerprint of breast cancer. Int J Biochem Cell Biol 2011 Jul;43(7):1010-20. Review. (IF=4.956).

  • Claudino WM, Quattrone A, Biganzoli L, Pestrin M, Bertini I, Di Leo A. Metabolomics: available results, current research projects in breast cancer, and future applications. J Clin Oncol. 2007 Jul 1;25(19):2840-6. (IF=18.970).

  • Di Leo A, Claudino W, Colangiuli D, Bessi S, Pestrin M, Biganzoli L. New strategies to identify molecular markers predicting chemotherapy activity and toxicity in breast cancer. Ann Oncol. 2007;18 Suppl 12:xii8-14. Review. (IF=6.452).

    Colorectal Cancer

  • Bertini I, Cacciatore S, Jensen BV, Schou JV, Johansen JS, Kruhøffer M, Luchinat C, Nielsen DL, Turano P. Metabolomic NMR fingerprinting to identify and predict survival of patients with metastatic colorectal cancer. Cancer Res. 2012 Jan 1;72(1):356-64. (IF=8.234).


Claudio luchinat cerm universit di firenze

Metabolomics @CERM/CIRMMP

Peridontal diseases

  • Mario Aimetti, Stefano Cacciatore, Antonio Graziano and Leonardo Tenori. Metabonomic analysis of saliva reveals generalized chronic periodontitis signature. Metabolomics; Online First™ (IF=3.608).

    Standard Operating Procedures

  • Bernini P, Bertini I, Luchinat C, Nincheri P, Staderini S, Turano P. Standard operating procedures for pre-analytical handling of blood and urine for metabolomic studies and biobanks. J Biomol NMR. 2011 Apr;49(3-4):231-43. (IF=3.047).

  • The future of medicine

  • Bertini I; Luchinat C; Tenori L. Metabolomics for the future of personalized medicine through information and communication technologies. PERSONALIZED MEDICINE Volume: 9 Issue: 2 (IF=0.783).


Claudio luchinat cerm universit di firenze

Our interest in metabolomics

  • Metabolic signature of individuals:

  • Metabolic phenotype

  • Metabolic signature of diseases

  • Coeliac disease

  • tumor  metastasis

  • heart failure, pulmonary diseases,etc…

  • Metabolites and biobank samples

  • Sensitive reporters of stability

  • Assess sample preparation and preanalytical procedures

  • SOP


Claudio luchinat cerm universit di firenze

Metabolomics steps

Handling and preparation of samples

NMR analysis

Metabolites identification

Statistical analysis

Data processing and bucketing


Claudio luchinat cerm universit di firenze

BioBank Project

  • Collect Store Processing

Distribute

Biological samples for scientific research


Claudio luchinat cerm universit di firenze

The Future of Medicine

The need for individual metabolomic screening

We are proposing to collect individual metabolomics data for a large screening of the Tuscany population


Claudio luchinat cerm universit di firenze

The FiorGen Foundation


Claudio luchinat cerm universit di firenze

FiorGen Foundation, a “non-profit organization of social utility” (ONLUS), was founded in 2002, with the purpose of favoring scientific, cultural and social development.

FiorGen Foundation is the result of a strong link between different scientific actors such as the Magnetic Resonance Center (CERM) of the Scientific Campus of Sesto Fiorentino and the Biomedical Campus of Careggi, which has been supported by the Chamber of Commerce, Industry and Handicrafts of Florence and the Ente Cassa di Risparmio of Florence.

How was FiorGen born


Claudio luchinat cerm universit di firenze

ADMINISTRATION COUNCIL

Vasco Galgani (President)

Calogero Surrenti (Vicepresident)

Gianni Amunni

Paolo Asso

Lucia Banci

Francesco Barbolla

Ivano Bertini

Gianfranco Gensini

Claudio Luchinat

SCIENTIFIC COMMITTEE

Ivano Bertini (President)

Rosanna Abbate

Andrea Galli

Maurizio Genuardi

Cristina Nativi

Governing Bodies


Claudio luchinat cerm universit di firenze

Charity auction “Art and Solidarity for the research”

 Campaign "Adopt a Researcher"

Fund Raising

CF: 94100210486


Claudio luchinat cerm universit di firenze

Communication

Newsletter FiorGenews

n. 1 n.2 n.3 n.4


Claudio luchinat cerm universit di firenze

Research Areas of FiorGen

  • Research Area 1: Bersagli e farmaci antitumorali

  • Agonisti di recettori nucleari nella modulazione della crescita ed invasività tumorale

  • Delezione organo specifica del recettore ARP-1 in modelli murini

  • Research Area 2: Fisiopatologia e farmacogenetica delle malattie cardiovascolari

  • Progetto Malattia Aneurismatica e Carotidea

  • Progetto variabilità nella risposta alla terapia antiaggregante (aspirina e clopidogrel)

  • Research Area 3: Origine malattie genetiche

  • Studio delle basi genetiche della predisposizione a neoplasie umane

  • Studi sull'origine della Sclerosi Laterale Amiotrofica

  • Caratterizzazione strutturale della proteina beta amiloide coinvolta nel morbo di Alzheimer

  • Research Area 4: Metabolomica

  • Research Area 5: BioBanca da Vinci European BioBank - daVEB

  • Research Area 6: Melanoma: nuovi possibili biomarcatori di diagnosi e progressione


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