WAR ON CANCER

1
Richard Milhous Nixon (January 9, 1913 April
22, 1994)

• WAR ON CANCER
• 1971. USA Kongress, National Cancer Act (R.
  Nixon).
• Virus Cancer Program

... by the year 1981
2
Trends in age-standardized lung cancer incidence
and death rates by sex, United States, 1975-2005
Jemal, A. et al. J. Natl. Cancer Inst. 2008
1001672-1694 doi10.1093/jnci/djn389
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Transformeerimata Transformeeritud
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Oncogenes
Normal genes (regulate cell growth)
1st mutation (leads to accelerated cell division)
1 mutation sufficient for role in cancer
development
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Tumor Suppressor Genes
Normal genes (prevent cancer)
1st mutation (susceptible carrier)
2nd mutation or loss (leads to cancer)
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Trends in age-standardized lung cancer incidence
and death rates by sex, United States, 1975-2005
Jemal, A. et al. J. Natl. Cancer Inst. 2008
1001672-1694 doi10.1093/jnci/djn389
10
Tüvirakud, kasvajarakud ja kasvaja tüvirakud
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Tüvirakk pluripotentne rakk, mis annab kahte
tüüpi järglasi endataolisi pluripotentseid
rakke ja diferentseerunud rakutüüpe.
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Pluripotentne (nt sisemine rakumass, ES rakud)
Totipotentne rakk (nt sügoot)
Multipotentne (nt hematopoeetilised tüvirakud)
Lõpuni diferentseerunud rakud (nt neuronid)
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Kasvaja tüvirakk on iseuuenev rakk, mille
järglasteks on samasugused tüvirakud ning
diferentseerunud rakud, mis moodustavad
kasvajate põhimassi. Neid on seni leitud
leukeemiatest, rinna, käärsoole, eesnäärme,
pankrease, pea ja kaela kasvajatest,
melanoomidest... jne.
15

• Kasvaja tüvirakud
• Parandavad väga efektiivselt DNA kahjustusi
  seega tekitavad resistentsuse kiiritusele
• Stimuleerivad angiogeneesi, produtseerides
  vajalikke faktoreid (näiteks VEGF).
• On lihtsalt migreeruvad, seega soodustavad
  metastaaside teket.

16
Julius Cohnheim (1839-1884) (1867) Kasvajad ei
teki mitte normaalsetest täiskasvanu rakkudest,
vaid embrüonaalsetest jäänukitest rakkudest,
mis on täiskasvanud organismis oma arengus maha
jäänud
Onkogenees on blokeeritud ontogenees
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A
B
C
D
E
F
Figure 1
control
nutlin
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G1
G2
pThr160
CDK2
CYCLIN E
pThr160
CDK2
CYCLIN A
s
Na-butyrate
nutlin
DIFFERENTIATION
Thr160
CDK2
CYCLIN E
p21
p53
Thr160
CDK2
CYCLIN A
X
Figure 9
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Neurons derived from reprogrammed fibroblasts
functionally integrate into the fetal brain and
improve symptoms of rats with Parkinson's
disease. Wernig M, Zhao JP, Pruszak J, Hedlund E,
Fu D, Soldner F, Broccoli V, Constantine-Paton M,
Isacson O, Jaenisch R. The Whitehead Institute
for Biomedical Research, Cambridge, MA 02142,
USA. The long-term goal of nuclear transfer or
alternative reprogramming approaches is to create
patient-specific donor cells for transplantation
therapy, avoiding immunorejection, a major
complication in current transplantation medicine.
It was recently shown that the four transcription
factors Oct4, Sox2, Klf4, and c-Myc induce
pluripotency in mouse fibroblasts. However, the
therapeutic potential of induced pluripotent stem
(iPS) cells for neural cell replacement
strategies remained unexplored. Here, we show
that iPS cells can be efficiently differentiated
into neural precursor cells, giving rise to
neuronal and glial cell types in culture. Upon
transplantation into the fetal mouse brain, the
cells migrate into various brain regions and
differentiate into glia and neurons, including
glutamatergic, GABAergic, and catecholaminergic
subtypes. Electrophysiological recordings and
morphological analysis demonstrated that the
grafted neurons had mature neuronal activity and
were functionally integrated in the host brain.
Furthermore, iPS cells were induced to
differentiate into dopamine neurons of midbrain
character and were able to improve behavior in a
rat model of Parkinson's disease upon
transplantation into the adult brain. We
minimized the risk of tumor formation from the
grafted cells by separating contaminating
pluripotent cells and committed neural cells
using fluorescence-activated cell sorting. Our
results demonstrate the therapeutic potential of
directly reprogrammed fibroblasts for neuronal
cell replacement in the animal model.
Proc Natl Acad Sci U S A. 2008 Apr
15105(15)5856-61
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Published online 24 January 2009 Nature
doi10.1038/news.2009.56 News Human embryonic
stem cell trial wins approval In a milestone for
a politically charged field, the US Food and Drug
Administration (FDA) has approved the world's
first clinical trial of a therapy generated by
human embryonic stem cells. Geron, a Menlo Park,
California-based company, announced on 23 January
that it has won the regulatory agency's approval
to launch a small, phase I safety study of a stem
cellderived therapy for spinal cord injury. In
the trial, eight to ten paralyzed individuals
within 7 to 14 days of their injury will be
injected at the point of injury with stem
cellderived precursors to oligodendrocytes,
which are key supportive cells in the central
nervous system. It is hoped that the cells will
lay down sheaths of myelin an insulator
essential for conducting nerve impulses around
injured neurons, as well as stimulating nerve
cells to regenerate. The cells have demonstrated
both capabilities in animals.1
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MILLEKS?
Table. Potential US Patient Populations for Stem
Cell-Based Therapies. Condition Number of
patients Cardiovascular disease 58
million Autoimmune diseases 30 million Diabetes
16 million Osteoporosis 10 million Cancers
8.2 million Alzheimers disease 5.5
million Parkinsons disease 5.5 million Burns
(severe) 0.3 million Spinal-cord injuries
0.25 million Birth defects 0.15
million/year Source Derived from Perry (2000)
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The Nobel Prize in Physiology or Medicine 2007
Mario R. Capecchi
Sir Martin J. Evans
Oliver Smithies
"for their discoveries of principles for
introducing specific gene modifications in mice
by the use of embryonic stem cells"
24
President Bushs veto on embryonic stem cell
development (2001) 2006 Senate approves a Stem
Cell Bill, Bushs veto
25
Palin has called herself "as pro-life as any
candidate can be and has called abortion an
"atrocity." Palin has stated that abortion should
be banned in nearly all cases, including rape and
incest, except if the life of the mother is
endangered. Palin has stated that she does not
support embryonic stem cell research.
26
2004 US presidential elections, blue - DEM, red -
REP
27
2008 US presidential elections, blue - DEM, red -
REP
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CONGREGATION FOR THE DOCTRINE OF THE
FAITH INSTRUCTION DIGNITAS PERSONAE ON CERTAIN
BIOETHICAL QUESTIONS
Rome, from the Offices of the Congregation for
the Doctrine of the Faith, 8 September 2008,
Feast of the Nativity of the Blessed Virgin Mary.
William Card. LevadaPrefect Luis F. Ladaria,
S.I.Titular Archbishop of ThibicaSecretary  
The use of embryonic stem cells or differentiated
cells derived from them even when these are
provided by other researchers through the
destruction of embryos or when such cells are
commercially available presents serious
problems from the standpoint of cooperation in
evil and scandal.
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She (the Church) reminds them that the ethical
value of biomedical science is gauged in
reference to both the unconditional respect owed
to every human being at every moment of his or
her existence, and the defense of the specific
character of the personal act which transmits
life.
30
Maimets T. Millal algab inimese elu? Akadeemia
(2008) 8, 1671-1694.
31

• MILLAL ALGAB INIMESE ELU?
• Jaapani maapiirkondades tekib inimene hetkel, kui
  vastsündinu teeb esimese häälitsuse.
• Gaana põhjaosas loetakse vastsündinu kui
  (täisväärtusliku) inimese tekkeks seitsmendat
  päeva pärast tema sündi.
• Ayatali põlisrahva seas (Taivanil) tekib
  inimeseks olemine alles siis, kui lapsele on
  nimi pandud see toimub kaks kuni kolm aastat
  pärast sündi.
• Mitmete indiaanisuguharude jaoks Mojave kõrbes
  algab inimelu siis, kui vastsündinu esimest korda
  rinda saab (Morowitz ja Trefil 1992).
• Antiikses Kreekas uskusid Pythagoras ja tema
  õpilased, et inimese hing tekib juba tema
  viljastamise hetkel ja niiviisi on see ka
  fikseeritud Hippokratese vandes.
• Platoni seisukohad lähtus keha ja hinge
  duaalsusest need on erinevad asjad. Platoni
  järgi algab inimese elu hetkel, kui kehasse
  siseneb hing. Järelikult peab inimeseks saamine
  toimuma mingil kindlal ajahetkel ning see ei saa
  toimuda paljuastmelise pikaajalise protsessina.
  Millal siis?
• Platon sünnihetkel
• Aristoteles poisslaps tekib neljakümnendal
  raseduse päeval, tütarlaps aga üheksakümnendal
  päeval

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• Seisukoht, et lootel ei teki hinge enne raseduse
  40. päeva, valitses hiljem Aquino Thomase, Hippo
  Augustinuse ja Püha Hieronymuse õpetuste kaudu
  pikalt ametlikku katoliiklikku mõtteviisi.
• 1558. aastal sätestas paavst Sixtus V, et
  karistuseks abordi või rasedusvastaste vahendite
  kasutamise eest on kirikust väljaheitmine.
• Tema järglane paavst Gregorius IX aga tõi tagasi
  endise seisukoha, et lõplikult valmimata
  (hingestamata) loote tapmine ei ole mõrv.
• See positsioon kestis aastani 1869, kui paavst
  Pius IX sätestas, et abort loote mistahes
  arengufaasis on inimese tapmine ja selle
  karistuseks kirikust väljaheitmine.
• G.W. Bush - dont fund, dont ban poliitika.
  09.08.2001.
• Erinevused religioonides

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Perinatal, Birth
Weeks 20-24EEG
Day 14 Gastrulation
Day 1 Fertilization
WHEN DOES HUMAN LIFE BEGIN? Scientific
Considerations
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Eesti Kirikute Nõukogu bioeetilised seisukohad
(2006) (http//www.ekklesia.ee/parnuimmaanuel/Rub
riik/bioeetilised_seisukohad.htm). ...iga
inimene on loodud Jumala näo järgi ja Tema
sarnaseks - see annab talle asendamatu väärtuse,
väärikuse ja pühaduse. Juba
viljastumisel saab tekkiv inimelu ainulaadse
geneetilise koodi.
EKNi liikmekirikud usuvad, et loodutena Jumala
näo järgi on kõik inimelud alates viljastumise
hetkest võrdselt väärtuslikud ja väärikad
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MIS ON GEEN?
Maimets T. Kas siniste silmade, valgete õite ja
haiguste geenid on olemas? Akadeemia (2005), 11,
2344-2384.
36
Gregor Johann Mendel (July 20, 1822 January 6,
1884)
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The word gene is completely free of any
hypothesis it expresses only the evident fact
that, in any case, many characteristics of the
organism are specified in the germ cells by
means of special conditions, foundations, and
determiners which are present in unique,
separate, and thereby independent ways - in
short, precisely what we wish to call genes.
Wilhelm Johannsen (1909)
Wilhelm Ludvig Johannsen born Feb. 3, 1857,
Copenhagen, Den.died Nov. 11, 1927, Copenhagen
GENOTÜÜP FENOTÜÜP
Johansseni jaoks on organismi fenotüüp kogu
genotüübi produkt, mis on tekkinud individuaalse
arengu käigus reaktsioonina keskkonnatingimustele.
Et genotüübi reaktsiooninormid on võimelised
plastiliselt kohanema erinevatele
keskkonnatingimustele, siis võivad fenotüübid
varieeruda kontiinuumina. Genotüübid varieeruvad
diskreetsetena, ent nende tulemused fenotüübi
tasemel teostuvad reaktsiooninormina
terviklikult Seega tuleks hoiduda rääkimast
mingi konkreetse tunnuse geenist, isegi
juhtudel, kus ei paista mingit ohtu nende
segiajamisele. Näiteks klassikalistes herneste
katsetes ei ole korrektne rääkida kollase
värvuse või kortsulisuse geenidest. Kollane
värv ja kortsud on vaid reaktsioonid teguritele,
millel võib olla hernetaimes veel palju muid
tagajärgi (Johannsen 1911).
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James Watson and Francis Crick, crackers of the
DNA code, in 1959
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GEEN DNA piirkond (nii kodeerivad DNA
järjestused, regulaatorjärjestused kui intronid),
mis kontrollib diskreetset pärilikku tunnust,
vastates tavaliselt ühele valgule või RNA-le
(Alberts et al 1994). DNA segment, mis on
seotud polüpetiidahela moodustamisega ta
sisaldab DNA järjestusi, mis eelnevad ja
järgnevad kodeerivatele järjestustele
(eksonitele) ning ka järjestusi viimaste sees
(intronid). (Lewin 1997) s.t. Geen
nukleotiidide järjestus.
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Figure 1 Nuclear-donor cat, and cloned kitten
with its surrogate mother. a, Adult female cat
that supplied cumulus cells for nuclear
transplantation. The cells were cultured in
DMEM/F12 medium for 5 days at 37 C until
confluent micromanipulation was used to
enucleate ova obtained after routine
ovariohysterectomy and to transfer the donor's
cumulus cells into the perivitelline space.
Enucleated ova and cumulus cells were fused by
electrofusion a second electropulse was applied
to activate the oocytes. b, The surrogate mother,
a synchronized recipient of three cloned embryos,
produced one cloned kitten, which was delivered
by caesarian section 66 days after embryonic
transfer.
Shin et al, Nature 415, 859 (2002)
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EPIGENEETIKA

• Kas kõik ikka on ära määratud DNA nukleotiidse
  järjestuse poolt?

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Mendels gene is more than just a DNA moiety
(T. Jenuwein and C.D. Allis, Science 293,
1074-1080, 2001)
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Scott F. Gilbert Tänane bioloog peab üheaegselt
mõtlema viies dimensioonis kolmes ruumimõõtmes,
evolutsiooni ja individuaalse arengu
(development) dimensioonis.