Molecular biomedicine

Doc. MUDr. Ing. RNDr. Peter Celec, DrSc., MPH

petercelec@gmail.com

www.imbm.sk

Linus Carl Pauling

(1901 – 1994)

Nobel prize

1954 – Chemistry

1962 – Peace

4

• „Life is a relationship between molecules, not

a property of any one molecule. So is therefore

disease, which endangers life. While there are

molecular diseases, there are no diseased

molecules.“

Linus C. Pauling, 1962

Francis Crick

(1916 – 2004)

Nobel prize

1962 – Physiology or medicine

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James Dewey Watson

(1928 – )

Nobel prize

1962 – Physiology or medicine

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9

1848

Ľudovít Štúr Johann Gregor Mendel

• Pathological anatomy

• Cell theory– Omnis cellula e cellula

Rudolf Virchow

• Biochemistry

• Proteins• Hemoglobin

Felix Hoppe-Seyler

Friedrich Miescher

Friedrich Miescher

• Pus from bandage

• Nuclein• Important for inheritance

Albrecht Kossel

• Theophylline

• Nobel prize 1910• Composition of nucleic acids• Adenine, guanine, cytosine, thymine

caffeine

sugar

bases

phosphate

Erwin Chargaff

Bases

Frederick Griffith

• In vivo experiments

• Pathogenic bacteria

• DNA and inheritance• Transforming factor

Osvald Avery

Frederick Sanger

(1918 – 2013)

Nobel prize

1958 – Chemistry

1980 – Chemistry

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Kary Banks Mullis

(1944 – )

Nobel prize

1993 – Chemistry

John Craig Venter(1946 - )

Francis Sellers Collins(1950 - )

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Genome (DNA)

Transcriptome (RNA)

Proteome (protein)

Metabolome (pathways)

Systems biology

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DNA is information !!!

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Information processing

• Communication

– Intercellular

– Intracellular

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Signalling pathways

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Reception

Ligands

• Hydrophilic

– Small molecules

– Larges proteins

• Hydrophobic

– Steroids

– Thyroxine

– Retinoids

Receptors

• G-protein coupled

• Tyrosine kinases

• Ion channels

• Intracellular

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Signalling pathways

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G-protein coupled

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Phosphate

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MAP kinases

GEF – Guanine Nucleotide Exchange Factor

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Second messangers

• cAMP

• cGMP

• IP3

• DAG

• Ca++

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Gene

• „The gene is by far the most sophisticated

program around.“

Bill Gates

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Nobel Prize in Chemistry 2006

Roger D. Kornberg

USA

Stanford University

b. 1947

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"for his studies of the molecular basis of eukaryotic transcription"

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Gene expression regulation

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Jak – Janus (Roman god of gates and doors) Kinase

Jak – Just Another Kinase

STAT – Signal Transducers and Activators of Transcription

APS – Adaptor protein with Pleckstrin homology and Src homology 2 domains

C-Cbl - Casitas B-lineage Lymphoma

EPO – Erythropoietin

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GR – Glucocorticoid Receptor

FKBP – FK506 (tacrolimus)-Binding Protein

HSP – Heat Shock Protein

GRE – Glucocorticoid Response Element

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TGACTCA

c-Fos – FBJ (Finkel MP, Biskis BO, Jinkins PB) OsteoSarcoma virus

AP-1 – Activator Protein 1

AP-1

FAP

FAP – c-Fos AP-1 binding site

IP-1 – Inhibitory Protein 1

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NFκB

FasL – Fas Ligand

TRAF – TNFα Receptor Associated Factor

NIK – NFκB Inducing Kinase

CBP – CREB Binding Protein

NFkB

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...but...

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Signalling pathways

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Responses???

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Cell death

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Apoptosis

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Autophagy

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Autophagy

• Microautophagy

• Macroautophagy

• Chaperone-mediated

– Pexophagy

– Mitophagy

– Xenophagy

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Oxygen sensingHIF – Hypoxia Inducible Factor

IGFR – Insulin like Growth Factor Receptor

EGFR – Epidermal Growth Factor Receptor

HER2 – Human Epidermal growth factor Receptor 2

PI3K – PhosphatidylInositol-3-Kinase

AKT – serine/threonine protein kinase B

FRAP – FKBP rapamycin associated protein

PH – Prolin Hydroxylases

HDAC – histone deacetylase

VHL – von Hippel-Lindau tumour suppressor protein

FIH – factor inhibiting HIF-1α

B – elongin B

C – elongin C

C2 – cullin 2

HRE – hypoxia response element

GLUT – glucose transporter

ARNT – Aryl hydrocarbon Receptor Nuclear Translocator

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Oxygen sensingHIF – Hypoxia Inducible Factor

IGFR – Insulin like Growth Factor Receptor

EGFR – Epidermal Growth Factor Receptor

HER2 – Human Epidermal growth factor Receptor 2

PI3K – PhosphatidylInositol-3-Kinase

AKT – serine/threonine protein kinase B

FRAP – FKBP rapamycin associated protein

PH – Prolin Hydroxylases

HDAC – histone deacetylase

VHL – von Hippel-Lindau tumour suppressor protein

FIH – factor inhibiting HIF-1α

B – elongin B

C – elongin C

C2 – cullin 2

HRE – hypoxia response element

GLUT – glucose transporter

ARNT – Aryl hydrocarbon Receptor Nuclear Translocator

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Angiogenesis

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Napoleone Ferrara

Genentech

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Aaron

Ciechanover

Avram

Hershko

Irwin

Rose

1/3 of the prize

Israel

1/3 of the prize

Israel

1/3 of the prize

USA

Technion – Israel

Instutute of

Technology

Haifa, Israel

Technion – Israel

Institute of

Technology

Haifa, Israel

University of California

Irvine, CA, USA

b. 1947 b. 1937

(Karcag, Hungary)

b. 1926

The Nobel Prize in Chemistry 2004"for the discovery of ubiquitin-mediated

protein degradation"

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Ub

E1

Ub

E2

Ub

E3

Ub

26S proteasome degradation

Target

UbUbUb

Ubiquitin pathway

Ubi-activating E Ubi-conjugating E Ubi-ligase

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Ub

ATP AMP + PPi

E1E1C

E2C

E2

E3C

E3

Protein K

Protein

E3

E3

Protein K

Protein K

E2

E3Protein K

E3

E2C

Ub

Protein

AMP + PPi

Protein K

Proteosynthesis

Antigen presentation

H

A

B

C1

C2

D

E

Ub

Protein

ATP

Protein

Protein

I

F

G

J

Nobel Prize in Physiology or Medicine 2007

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Mario R. Capecchi Sir Martin J. Evans Oliver Smithies

1/3 of the prize 1/3 of the prize 1/3 of the prize

USA United Kingdom USA

University of Utah Salt Lake City, UT, USA; Howard Hughes Medical Institute

Cardiff University Cardiff, United Kingdom

University of North Carolina at Chapel Hill Chapel Hill, NC, USA

b. 1937(in Italy)

b. 1941b. 1925(in United Kingdom)

"for their discoveries of

principles for introducing

specific gene modifications

in mice by the use of

embryonic stem cells"

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Causes of death

• Ľudovít Štúr

• Johann Gregor Mendel

• Friedrich Miescher

• Rudolf Virchow

• Albrecht Kossel

• Oswald Avery

• Erwin Chargaff

• Francis Crick

• sepsis (40y)

• nephritis (61y)

• tuberculosis (51y)

• trombosis (80y)

• infarction (73y)

• cancer (77y)

• heart failure (96y)

• cancer (88y)

Pathophysiology

Disease

Interactions

Environment

Genes

Heritability

large

Disease

Interactions

Environment

Genes

small

Disease

Interactions

EnvironmentGenes

NGS

Indivdualized medicine

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Individualized medicine

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Dennis Lo

• Fetus is similar to a tumor• Non-invasive prenatal diagnosis

– Sex– RhD– Aneuploidies– Fetal genome

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Synthetic biology

Gene therapy

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Gene therapy

Shinya Yamanaka

(1962 – )

Nobelova cena

2012 – Fyziológia alebo medicína

iPSC

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Shinya Yamanaka

Kyoto University

iPS

• Reprogramming of differentiated cells

• Pluripotency

• No immune response

• Without retroviral vectors

• Without oncogenes

Parabiosis

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Prevention of wrong advices

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Individualized medicine

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Personalized medicine

23andme

23andme

Better not to know?

Preventive medicine

Physicians are afraid of wrong interpretations

Cholesterol? Blood pressure?

Fear comes from the unknown

www.imbm.sk

petercelec@gmail.com