nks and cancer ilan r. kirsch, m.d. 23 april 2004 nks 2004
TRANSCRIPT
Ph.D. Physics Princeton (John Wheeler)subsequently M.D., HarvardInternal Medicine, Massachusetts General Hospital (MGH)Currently a distinguished Physician at MGH
Background to dissenting opinion #1:
• “I know very, very little about this area. I am aware of Wolfram and, (…), my initial reaction was to think that it was an elaborate fantasy.”
• “Particle physicists like to say that the theory of complexity is the most exciting new thing in science in a generation, except that it has the one disadvantage of not existing”(Steven Weinberg, New York Review of Books, October 24, 2002)
Asst. Prof. Computer Sciences - MITsubsequently M.D., HarvardEmergency medicineFDANow an independent consultant
Background to dissenting opinion #2:
“Ed Fredkin is one of the 2 or 3 smartest people I’ve ever met, and what I’ve heard about Wolfram is consistent with his being equally clever. Still, I was skeptical about Fredkin’s stuff half my life ago, and I’m skeptical about Wolfram’s stuff now. Unfortunately, getting into a discussion of this material is a little like talking about the predictions of Nostradamus, or about nonstandard theories of the assassination of John Kennedy. The skepticism is based on a simple meta-argument: The new theory, if it is correct, should be able to predict things we didn’t already know, not just fit a model with many, many degrees of freedom to an arbitrary selection from the great body of old data.”
“There is something unique about theoretical physics, making me even more skeptical about extending the cellular-automata model to other areas. In physics, most people seem to believe that the reality is going to turn out to be simple (in the sense of having only a few different kinds of components), but weirder and weirder, perhaps to the point of incomprehensibility to humans. Maybe cellular automata will be useful here, as yet another (misleading, but not totally misleading) metaphor. On the other hand, in most other parts of science everyone seems to believe that the reality is going to stay complex, less and less weird as knowledge grows, but just too damn detailed. I’m not sure that metaphors have ever been of very much value in such circumstances.”
• Cancer as a starting point for historical/philosophical inquiry
• Cancer as a basis for the study of growth and development
• Cancer as a basis for the study of evolution
• Cancer as a model of targeted therapy
• Cancer as a platform for the implementation of technology
• Cancer as a microcosm of health care concerns
Adenoma Carcinoma Sequence Normal Early Intermediate Advanced Cancer
Mucosa Adenoma Adenoma Adenoma
5-20 yrs 5-15 yrs
APC,bcl-2, c-myc,Hypomethylation,
ß-catenin
K-rasSMAD 2,SMAD 4
p53
MSH2,MLH1, MSH6,PMS1,PMS2
Adapted from Ilyas et al. Eur. J. Cancer 1999; 35:335-351 and Kelloff et al. Oncology 1996; 10:1471-1484Adapted from Ilyas et al. Eur. J. Cancer 1999; 35:335-351 and Kelloff et al. Oncology 1996; 10:1471-1484
NCI60 panel of cancer cell linesLung Ovarian Breast Renal
NCI-H23 Adeno OVCAR-3 MCF-7 UO-31
NCI-H522 Adeno OVCAR-4 NCI/ADR-RES SN12C
A549 Adeno OVCAR-5 HS-578T A498
EKVX Adeno OVCAR-8 MDA-MB-231 CAKI-1
HOP-62 Adeno IGROV-1 MDA-MB-435 RXF 393
HOP-92 Lg.C. SKOV-3 MDA-N * ACHN
NCI-H460 Lg.C. BT-549 786-0
NCI-H226 Squ. Hematological T-47D TK-10
NCI-H322M Br.A. K562 CML
MOLT-4 ALL Colon Melanoma
CNS CCRF-CEM ALL HT29 SK-MEL-2
SF-268 HL-60 PML HCT-116 SK-MEL-5 Premel.
SF-295 RPMI 8226 MM HCC-2998 SK-MEL-28
SF-539 SR Lg. Cell SW-620 MALME-3M
U251 COLO 205 LOX IMVI
SNB-19 Prostate HCT-15 UACC-62
SNB-75 DU-145 KM 12 UACC-257
PC-3 M14
+3n
0
23
46
69
92
115
138
KM12
HCC-2998HCT-15
HL-60(TB)HCT-116
SR
UO-31
NCI-H322MCCRF-CEM
SW-620NCI-H522
ACHNU251
NCI-H460OVCAR-5MDA-MB-
SNB-75OVCAR-8
SF-268NCI-H23HS 578T
MDA-MB-
T-47DRXF-393DU-145
M14SNB-19
NCI-H226A549/ATCC
EKVX
RPMI-8226
SN12C
LOX IMVI
K-562MCF7HT29CAKI-1
OVCAR-3OVCAR-4UACC-257
BT-549COLO 205UACC-62
A498TK-10
MALME-SK-MEL-2
786-0
SK-OV-3IGROV1
PC-3SF-539
SK-MEL-28
HOP-92MOLT-4SK-MEL-5
HOP-62SF-295
Cell lines
Modal chromosome number
+5n
+4n
+3n
+2n
Ploidy
Numerical abnormalities
0
5
10
15
20
25
30
HCT-15
CCRF-CEM
SR
HCT-116HL-60(TB)HCC-2998
SW-620UO-31
SK-OV-3NCI-H460
SF-268MOLT-4
U251KM12ACHNIGROV1
UACC-62
A549/ATCC
HT29M14
NCI-H522OVCAR-5
K-562CAKI-1
MDA-MB-435
DU-145NCI-H23
SNB-19SNB-75
RPMI-8226LOX IMVIUACC-257
MCF7T-47DEKVX
OVCAR-3OVCAR-4BT-549HS 578T
MDA-MB-
PC-3
OVCAR-8NCI-H226RXF-393
NCI-H322MCOLO 205
MALME-3MSK-MEL-28
SN12CA498
TK-10SF-539786-0
SF-295HOP-92
SK-MEL-2SK-MEL-5HOP-62
Cell lines
Number of numerical changes
0
5
10
15
20
25
30
HCT-15HCT-116
CCRF-CEM
SR
HL-60(TB)HCC-2998SW-620
UO-31SK-OV-3
MOLT-4NCI-H460
SF-268KM12U251ACHN
IGROV1UACC-62
HT29
A549/ATCC
M14
MDA-MB-435
OVCAR-5NCI-H522DU-145CAKI-1
RPMI-8226
MCF7
UACC-257NCI-H23LOX IMVI
T-47DSNB-75SNB-19
OVCAR-4OVCAR-3BT-549
EKVX
MDA-MB-HS 578T
PC-3
OVCAR-8RXF-393NCI-H226
NCI-H322MMALME-3MCOLO 205SK-MEL-28
A498SN12CSF-539
786-0SF-295
SK-MEL-2HOP-62
Cell lines
Changes of chromosome number
Numerical complexity Numerical heterogeneity
NH correlates with the number of numerical aberrations in the cell line (r=0.53, P<0.01)
Structural rearrangements
0
5
10
15
20
25
30
35
40
45
50
ACHN
CCRF-CEM
SNB-75MOLT-4
SR
HCT-15UO-31
A549/ATCHCT-116HCC-2998
KM12
MALME-NCI-H460
786-0
NCI-H522IGROV1SNB-19
UACC-62UACC-257HL-60(TB)
CAKI-1
LOX IMVI
M14
BT-549SF-295
COLO 205
A498TK-10
OVCAR-5
K-562HT29SW-620
SK-MEL-2SK-MEL-5NCI-H226SK-OV-3
T-47DDU-145HOP-62RXF-393
U251SF-268
RPMI-8226MDA-MB-HS 578T
MDA-MB-SK-MEL-28
EKVX
NCI-H23HOP-92SN12CSF-539
PC-3
OVCAR-3OVCAR-4
MCF7
OVCAR-8
NCI-
Cell lines
Number of structurally rearranged chromosomes
per cell line
1 rearranged chromosome – ACHN45rearranged chromosomes – NCI-H322M
Structural complexity
0
10
20
30
40
50
ACHN
CCRF-CEM
MOLT-4
SR
HCT-15UO-31SNB-75
A549/ATCC
HCT-116HCC-2998
KM12
MALME-3MNCI-H460
786-0
NCI-H522UACC-257
UACC-62IGROV1SNB-19
HL-60(TB)
CAKI-1LOX IMVI
BT-549
M14A498
COLO 205
TK-10SF-295
OVCAR-5
K-562HT29
SW-620SK-MEL-2SK-MEL-5
T-47DDU-145
NCI-H226SK-OV-3RXF-393HOP-62U251
MDA-MB-RPMI-8226
SF-268
MDA-MB-435
HS 578TSK-MEL-28
EKVXSN12CHOP-92NCI-H23SF-539
PC-3
OVCAR-3OVCAR-4
MCF7
OVCAR-8NCI-H322M
Cell lines
Clonal structurally rearranged
chromosomes
Structural heterogeneity
0
1
2
3
4
5
6
7
8
ACHN
CCRF-CEM
MOLT-4
SR
HCT-15UO-31
SNB-75
A549/ATCC
HCT-116HCC-2998
KM12
MALME-3MNCI-H460
786-0
NCI-H522UACC-257
UACC-62IGROV1SNB-19
HL-60(TB)
CAKI-1LOX IMVI
BT-549
M14A498
COLO 205
TK-10SF-295
OVCAR-5
K-562HT29
SW-620SK-MEL-2SK-MEL-5
T-47DDU-145
NCI-H226SK-OV-3RXF-393HOP-62
U251
MDA-MB-RPMI-8226
SF-268
MDA-MB-435
HS 578T
SK-MEL-28
EKVXSN12CHOP-92NCI-H23SF-539PC-3
OVCAR-3OVCAR-4
MCF7
OVCAR-8NCI-H322M
Cell lines
Non-clonal structurally rearranged chromosomes
(per cell)
Cell lines Tissue Ploidy SC NC SH NHCCRF-CEM LEUKEMIA 2 MOLT-4 LEUKEMIA 4 SR LEUKEMIA 2 HL-60(TB) LEUKEMIA 2 K-562 LEUKEMIA 3 HCT-116 COLON 2 HCT-15 COLON 2 HCC-2998 COLON 2 KM12 COLON 2 SW-620 COLON 2 HT29 COLON 3 COLO 205 COLON 3 ACHN RENAL 2 UO-31 RENAL 2 CAKI-1 RENAL 3 786-0 RENAL 4 A498 RENAL 3 TK-10 RENAL 4 RXF-393 RENAL 3 SN12C RENAL 3
NCI-H460 LUNG 2 NCI-H522 LUNG 2 A549/ATCC LUNG 3 NCI-H226 LUNG 3 NCI-H322M LUNG 2 NCI-H23 LUNG 2 HOP-62 LUNG 4 EKVX LUNG 3 HOP-92 LUNG 4 IGROV1 OVARIAN 4 SK-OV-3 OVARIAN 4 OVCAR-5 OVARIAN 2 OVCAR-3 OVARIAN 3 OVCAR-4 OVARIAN 3 OVCAR-8 OVARIAN 2 RPMI-8226 MYELOMA 3
UACC-257 MELANOMA 3 UACC-62 MELANOMA 3 MALME-3M MELANOMA 4 LOX IMVI MELANOMA 3 M14 MELANOMA 3 SK-MEL-2 MELANOMA 4 SK-MEL-5 MELANOMA 4 SK-MEL-28 MELANOMA 4 T-47D BREAST 2 MDA-MB-435 BREAST 2 MCF7 BREAST 3 BT-549 BREAST 3 MDA-MB-231/ATCC BREAST 2 HS 578T BREAST 3 DU-145 PROSTATE 3 PC-3 PROSTATE 4 SNB-75 CNS 2 SNB-19 CNS 3 U251 CNS 2 SF-268 CNS 2 SF-295 CNS 5 SF-539 CNS 4
Karyotypic complexity of the NCI-60 (organized by lineage)
Cell lines Tissue Ploidy SC NC SH NHHCT-116 COLON 2 CCRF-CEM LEUKEMIA 2 HCT-15 COLON 2 MOLT-4 LEUKEMIA 4 ACHN RENAL 2 SR LEUKEMIA 2 UO-31 RENAL 2 HCC-2998 COLON 2 KM12 COLON 2 NCI-H522 LUNG 2 A549/ATCC LUNG 3 HL-60(TB) LEUKEMIA 2 IGROV1 OVARIAN 4 UACC-257 MELANOMA 3 SW-620 COLON 2 HT29 COLON 3 SNB-75 CNS 2 SK-OV-3 OVARIAN 4 T-47D BREAST 2 DU-145 PROSTATE 3 OVCAR-5 OVARIAN 2 LOX IMVI MELANOMA 3 M14 MELANOMA 3 K-562 LEUKEMIA 3 UACC-62 MELANOMA 3 NCI-H460 LUNG 2 SNB-19 CNS 3 MALME-3M MELANOMA 4 CAKI-1 RENAL 3 COLO 205 COLON 3 A498 RENAL 3 OVCAR-3 OVARIAN 3 MDA-MB-435 BREAST 2 MCF7 BREAST 3 RPMI-8226 MYELOMA 3 OVCAR-4 OVARIAN 3 OVCAR-8 OVARIAN 2 NCI-H226 LUNG 3 BT-549 BREAST 3 MDA-MB-231/ATCC BREAST 2 786-0 RENAL 4 TK-10 RENAL 4 U251 CNS 2 NCI-H322M LUNG 2 NCI-H23 LUNG 2 HS 578T BREAST 3 PC-3 PROSTATE 4 SF-268 CNS 2 SF-295 CNS 5 SK-MEL-2 MELANOMA 4 SK-MEL-5 MELANOMA 4 HOP-62 LUNG 4 EKVX LUNG 3 RXF-393 RENAL 3 SN12C RENAL 3 HOP-92 LUNG 4 SK-MEL-28 MELANOMA 4 SF-539 CNS 4
Karyotypic complexity of the NCI-60 (organized from less to more)
Cancer Risk is a Function of:
• inheritance and inherent physiology
• environmental influences
• randomness (fate)
Does a probabilistic model partially solve the problem or just
reduce the problem from the level of a pattern of cells to the
level of a single cell?
“There is something unique about theoretical physics, making me even more skeptical about extending the cellular-automata model to other areas. In physics, most people seem to believe that the reality is going to turn out to be simple (in the sense of having only a few different kinds of components), but weirder and weirder, perhaps to the point of incomprehensibility to humans. Maybe cellular automata will be useful here, as yet another (misleading, but not totally misleading) metaphor. On the other hand, in most other parts of science everyone seems to believe that the reality is going to stay complex, less and less weird as knowledge grows, but just too damn detailed. I’m not sure that metaphors have ever been of very much value in such circumstances.”