NKS and Cancer

Ilan R. Kirsch, M.D.

23 April 2004

NKS 2004

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

Cancer is a genetic disease

caused by genetic instability

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

The nature and essence of mutational events…

SKOV-3SKOV-3

Karyotypic complexity • Ploidy

• Numerical abnormalities

• Structural rearrangements

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)

Todd Rowland - Wolfram Science

Rule 250 with mutated cell (white to black) creating BBB configuration

Cancer Risk is a Function of:

• inheritance and inherent physiology

• environmental influences

• randomness (fate)

Is cancer (and therefore all biology) “predetermined”?

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.”

• Deep simplicity: Chaos, Complexity, and the Emergence of Life by John Gribben(biology is as fundamentally predictable as physics)

• The Fabric of the Cosmos Space, Time, and the Texture of Realityby Brian Greene(physics (e.g. quantum mechanics) is as fundamentally unpredictable as biology)