🚀 go-pugleaf

Le lun, 07 nov 2011 17:46:37, John a plopp�:
> Animations of a Possible Cure for Cancer
> 
> This is an approach to the cure or treatment of cancer using a
> relatively simple mathematical algorithm.
> 
> http://math-blog.com/2011/10/31/animations-of-a-possible-cure-for-cancer/

That is a nice animation but has little to no merit as far as curing 
cancer goes. Not all cancer cells are aneuploid, nor is every normal 
cell diploid. Bacteriophages target bacteries, not mamalian cells, 
although it would be possible to find another vector, like a lentivirus.
But in that case it would be much easier to target only cancer cells
based on the surface receptor they display. Which, surprise surprise,
is already being studied.
The surface recognition strategy is also used by our own immune
system to eliminate most cancer cells (some escape from time to time),
or in therapeutic strategies based on autologous immune cells modified
to kill the (escaped) cancer cells -already in use.

The problem with using a virus is that it usually triggers the immune
response, which can lead, in the best case scenario, to the destruction
of the therapeutic vector, and in the worst case, to very toxic effects.

Basing the system on the number of chromosome is typically a bad idea as
exposed higher (this is a common mistake: most cancer cells are aneuploid,
so let's kill all the non-diploid cells. Cancer cured. It amounts to 
Most cancer cells are alive, so let's kill all live cells, cancer cured.)
Not to mention that it would be extremely difficult to "automatically"
count the number of chromosomes. Telomeres and centromeres vary in size 
and "geometry" between cell types, depending on the age, etc...

As I said, that's a nice animation.

-- 
PiLS

On Nov 8, 2:34 pm, PiLS <p...@invalid.ca> wrote:
> Le lun, 07 nov 2011 17:46:37, John a ploppé:
>
> > Animations of a Possible Cure for Cancer
>
> > This is an approach to the cure or treatment of cancer using a
> > relatively simple mathematical algorithm.
>
> >http://math-blog.com/2011/10/31/animations-of-a-possible-cure-for-can...
>
> That is a nice animation but has little to no merit as far as curing
> cancer goes. Not all cancer cells are aneuploid, nor is every normal
> cell diploid. Bacteriophages target bacteries, not mamalian cells,
> although it would be possible to find another vector, like a lentivirus.
> But in that case it would be much easier to target only cancer cells
> based on the surface receptor they display. Which, surprise surprise,
> is already being studied.
> The surface recognition strategy is also used by our own immune
> system to eliminate most cancer cells (some escape from time to time),
> or in therapeutic strategies based on autologous immune cells modified
> to kill the (escaped) cancer cells -already in use.
>
> The problem with using a virus is that it usually triggers the immune
> response, which can lead, in the best case scenario, to the destruction
> of the therapeutic vector, and in the worst case, to very toxic effects.
>
> Basing the system on the number of chromosome is typically a bad idea as
> exposed higher (this is a common mistake: most cancer cells are aneuploid,
> so let's kill all the non-diploid cells. Cancer cured. It amounts to
> Most cancer cells are alive, so let's kill all live cells, cancer cured.)
> Not to mention that it would be extremely difficult to "automatically"
> count the number of chromosomes. Telomeres and centromeres vary in size
> and "geometry" between cell types, depending on the age, etc...
>
> As I said, that's a nice animation.
>
> --
> PiLS

As the article indicates, the presentation is simplified and a number
of technical difficulties are omitted to present the basic concept of
how one might successfully "count" the number of chromosomes and kill
cells with the wrong number of chromosomes.

For example, in the actual system, the non-toxic precursor might be
engineered to react specifically with the end of the telomeres since,
indeed, they vary in length by many accounts.  A telomere is
supposedly constructed of repeating DNA sequences, e.g.

(repeat)(repeat)(repeat)(repeat)...(repeat)(repeat)(repeat)(end of
DNA)

so one might engineer the precusor to target the end pattern:

(repeat)(repeat)(repeat)(end of DNA) only.

or some other solution.  Something similar may be possible with the
centromeres or other commonly recognized features of the chromosomes.
As with the telomeres, the edge of a commonly recognized feature may
be constant even though the size and geometry of the feature varies.

Red blood cells have no chromosomes, so the system would generate no
toxins in the red blood cells.  Terminally ill persons probably would
be willing to sacrifice their sperm or ova if some way to protect
these cells, which lack the normal number of chromosomes, could not be
found.  Osteoblasts and muscle cells reportedly have multiple nuclei,
so in the real system one would like the drains to reach or be a
natural part (preferred) of the nucleus and perform the selective
destruction operation, the bathtub mechanism, inside the nuclear
membrane so cells with multiple normal nuclei would survive.

The implementation of this system is technically advanced, so one
would be talking about modifying the bacteriophages to work with human
cells or using lentiviruses or some other mechanism of introducing the
drains into the cells.  It would be better to find a constant feature
that is present in the cells naturally and could be used as the drain.

Yes, cancer researchers have been trying to use receptors on the
exterior of cancer cells for some time to cure or treat the disease,
with dismal results in the real world.  The same could be said of
attempts to harness the immune system.  So, instead, the article
presents a different approach that hasn't been tried and failed many
many times.

The relationship between aneuploidy and cancer is unclear, as the
article clearly states.

I am not a biologist and I would urge biologists with specific
expertise to think about how to implement the illustrated algorithm in
a real system using real cellular and molecular building blocks,
viruses, and other components that we have knowledge of.


Sincerely,

John

On Nov 8, 2:34 pm, PiLS <p...@invalid.ca> wrote:
> Le lun, 07 nov 2011 17:46:37, John a ploppé:
>
> > Animations of a Possible Cure for Cancer
>
> > This is an approach to the cure or treatment of cancer using a
> > relatively simple mathematical algorithm.
>
> >http://math-blog.com/2011/10/31/animations-of-a-possible-cure-for-can...
>
> That is a nice animation but has little to no merit as far as curing
> cancer goes. Not all cancer cells are aneuploid, nor is every normal
> cell diploid. Bacteriophages target bacteries, not mamalian cells,
> although it would be possible to find another vector, like a lentivirus.
> But in that case it would be much easier to target only cancer cells
> based on the surface receptor they display. Which, surprise surprise,
> is already being studied.
> The surface recognition strategy is also used by our own immune
> system to eliminate most cancer cells (some escape from time to time),
> or in therapeutic strategies based on autologous immune cells modified
> to kill the (escaped) cancer cells -already in use.
>
> The problem with using a virus is that it usually triggers the immune
> response, which can lead, in the best case scenario, to the destruction
> of the therapeutic vector, and in the worst case, to very toxic effects.
>
> Basing the system on the number of chromosome is typically a bad idea as
> exposed higher (this is a common mistake: most cancer cells are aneuploid,
> so let's kill all the non-diploid cells. Cancer cured. It amounts to
> Most cancer cells are alive, so let's kill all live cells, cancer cured.)
> Not to mention that it would be extremely difficult to "automatically"
> count the number of chromosomes. Telomeres and centromeres vary in size
> and "geometry" between cell types, depending on the age, etc...
>
> As I said, that's a nice animation.
>
> --
> PiLS

With respect to bacteriophages, see, for example, this article:

(The FASEB Journal. 1999;13:727-734.)
© 1999 FASEB


--------------------------------------------------------------------------------

Research Communications

Gene transfer to mammalian cells using genetically targeted
filamentous bacteriophage
DAVID LAROCCA, PAUL D. KASSNER, ALISON WITTE, ROBERT CHARLES LADNERa,
GLENN F. PIERCE and ANDREW BAIRD
Selective Genetics Inc., San Diego, California 92121, USA; and

a Dyax Corporation, Cambridge, Massachusetts 02115, USA

We have genetically modified filamentous bacteriophage to deliver
genes to mammalian cells. In previous studies we showed that
noncovalently attached fibroblast growth factor (FGF2) can target
bacteriophage to COS-1 cells, resulting in receptor-mediated
transduction with a reporter gene. Thus, bacteriophage, which normally
lack tropism for mammalian cells, can be adapted for mammalian cell
gene transfer. To determine the potential of using phage-mediated gene
transfer as a novel display phage screening strategy, we transfected
COS-1 cells with phage that were engineered to display FGF2 on their
surface coat as a fusion to the minor coat protein, pIII. Immunoblot
and ELISA analysis confirmed the presence of FGF2 on the phage coat.
Significant transduction was obtained in COS-1 cells with the targeted
FGF2-phage compared with the nontargeted parent phage. Specificity was
demonstrated by successful inhibition of transduction in the presence
of excess free FGF2. Having demonstrated mammalian cell transduction
by phage displaying a known gene targeting ligand, it is now feasible
to apply phage-mediated transduction as a screen for discovering novel
ligands.—Larocca, D., Kassner, P. D., Witte, A., Ladner, R. C.,
Pierce, G., Baird, A. Gene transfer to mammalian cells using
genetically targeted filamentous bacteriophage.



http://www.fasebj.org/content/13/6/727

Sincerely,

John

If you're going to target chromatids (as you would be doing in the
<repeat><repeat><repeat><END> example, it's worth noting that you'd
kill any dividing cell. Chemotherapy does that to a certain extent,
but for very limited periods of time (and it makes the patients
VERY sick). For any prolonged period of time it would simply kill 
the patient.
In addition, terminally ill patients may be willing to sacrifice gametes,
but killing the megacaryocytes would be a BAD thing (not that it would 
matter if you killed the dividing cells to begin with of course, as the 
patient would be dead before the platelet count dropped so low as to 
cause massive,letal haemorrhage).
When you say that harnessing the immune system to target surface antigens
failed, what are you referring to? We just started trying! 
Or is there some precedent that I am not aware of? (entirely possible).
Targetting chromosomes is a bad idea. Nature plays to much with them, 
and they already have their own very fine regulatory mechanisms.
(most cells do't survive accidental aneuplo�dy already).
In addition, not all cancer cells are aneuplo�d. In fact, in most cases
aneuplo�dy is probably only a side-effect of the cancer cells being 
"immortal" already (so accidental aneuploidy is not eliminated as it
usually is). So my opinion is that targetting aneuploid cells would 
NOT cure cancer (arguably the most important flaw in the system).

-- 
PiLS
Everything is worth discussing

On Nov 14, 8:44 am, PiLS <p...@invalid.ca> wrote:
> If you're going to target chromatids (as you would be doing in the
> <repeat><repeat><repeat><END> example, it's worth noting that you'd
> kill any dividing cell. Chemotherapy does that to a certain extent,
> but for very limited periods of time (and it makes the patients
> VERY sick). For any prolonged period of time it would simply kill
> the patient.
> In addition, terminally ill patients may be willing to sacrifice gametes,
> but killing the megacaryocytes would be a BAD thing (not that it would
> matter if you killed the dividing cells to begin with of course, as the
> patient would be dead before the platelet count dropped so low as to
> cause massive,letal haemorrhage).
> When you say that harnessing the immune system to target surface antigens
> failed, what are you referring to? We just started trying!
> Or is there some precedent that I am not aware of? (entirely possible).
> Targetting chromosomes is a bad idea. Nature plays to much with them,
> and they already have their own very fine regulatory mechanisms.
> (most cells do't survive accidental aneuplo dy already).
> In addition, not all cancer cells are aneuplo d. In fact, in most cases
> aneuplo dy is probably only a side-effect of the cancer cells being
> "immortal" already (so accidental aneuploidy is not eliminated as it
> usually is). So my opinion is that targetting aneuploid cells would
> NOT cure cancer (arguably the most important flaw in the system).
>
> --
> PiLS
> Everything is worth discussing

Greetings,

I envision the harmless precursor interacting with a drain feature on
or associated with the chromosome, such as the end of the chromosome.
The drain feature acts as a catalyst with respect to the harmless
precursor, breaking it apart or transforming it into a toxin.  This
would not necessarilly kill the dividing cell.  Indeed, if the drain
feature changes geometry during cell division, it may be possible to
engineer the reaction to occur only when the cell is not dividing.

I don't know about surface antigens specifically but there have been
many many attempts to harness the immune system at least since the
1970s with consistently disappointing results.

The relationship between cancer and aneuploidy is not well understood.
Yes, I agree this is the most serious issue with the approach, as I
state in the article.

If, for example, aneuploidy only causes the rapid mutation and thus
adaptation of the cancer cells, then killing the aneuploid cells by
itself would only reduce the malginanacy without curing the disease.
However, the surviving cells would not adapt to anti-cancer agents as
is currently believed to be the case.  So a combination of a system
that kills the aneuploid cells and something else, perhaps even a
currently known drug, might cure the disease.

For the purpose of the successful treatment or cure of cancer, whether
aneuploidy is a cause or consequence of cancer may be an academic
question. If we can find a feature that is always or frequently
present in cancer cells or even predictably associated with highly
malignant cancer cells and never or rarely present in normal cells,
this feature can be used to selectively kill cancer cells or, at
least, highly malignant cancer cells, curing or effectively treating
the disease.

If cancer has a single unified cause, it is logical to seek this
single cause. If cancer has many specific causes, it may be more
effective to seek some common trait shared by the many variants of
cancer, something that is a consequence rather than a cause.

Penicillin and many other antibiotics are effective because they
attack a feature shared by the many different bacteria that cause
bacterial pneumonias and other diseases, even though the specific
causes of bacterial pneumonia and other diseases are many different
kinds of bacteria — which differ at the genetic level.

Some scientific references on aneuploidy and cancer

URL: http://www.sciencemag.org/content/333/6045/942.summary

Science 19 August 2011:
Vol. 333 no. 6045 pp. 942-943
DOI: 10.1126/science.1211154

Aneuploidy Drives a Mutator Phenotype in Cancer

Richard D. Kolodner, Don W. Cleveland, Christopher D. Putnam
+ Author Affiliations
Ludwig Institute for Cancer Research, University of California San
Diego School of Medicine, La Jolla, CA 92093-0660, USA.
E-mail: rkolodner@ucsd.edu, dcleveland@ucsd.edu, cdputnam@ucsd.edu

Summary

The association of chromosomal abnormalities with cancer—including
chromosome translocations, deletions, amplifications, and
inappropriate numbers of chromosomes (aneuploidy)—has been known for
more than a century. Even karyotypically stable cancers are
genetically abnormal because of high frequencies of point mutations.
Despite our current understanding of cancer genomes, it has been
difficult to determine whether many genetic abnormalities are a cause
or consequence of carcinogenesis. Increased missegregation of whole
chromosomes prior to the final steps of cell division (mitosis)
generates aneuploidy and can promote tumorigenesis in some genetic
contexts in mice (1), as the German biologist Theodor Boveri initially
proposed more than 100 years ago. Two papers in this issue, by
Sheltzer et al. (2) on page 1026 and Solomon et al. (3) on page 1039,
show that aneuploidy enhances genetic recombination and defective DNA
damage repair, thereby providing a mechanistic link between aneuploidy
and genomic instability.
The editors suggest the following Related Resources on Science sites
In Science Magazine

Aneuploidy Drives Genomic Instability in Yeast

Jason M. Sheltzer, Heidi M. Blank, Sarah J. Pfau, Yoshie Tange, Benson
M. George, Timothy J. Humpton, Ilana L. Brito, Yasushi Hiraoka, Osami
Niwa, and Angelika Amon
Science 19 August 2011: 1026-1030.
Mutational Inactivation of STAG2 Causes Aneuploidy in Human Cancer
David A. Solomon, Taeyeon Kim, Laura A. Diaz-Martinez, Joshlean Fair,
Abdel G. Elkahloun, Brent T. Harris, Jeffrey A. Toretsky, Steven A.
Rosenberg, Neerav Shukla, Marc Ladanyi, Yardena Samuels, C. David
James, Hongtao Yu, Jung-Sik Kim, and Todd Waldman
Science 19 August 2011: 1039-1043.

URL: http://www.nature.com/nature/journal/v446/n7131/full/446038a.html

Nature 446, 38-39 (1 March 2007) | doi:10.1038/446038a; Published
online 28 February 2007
Cell biology: Aneuploidy and cancer
By David Pellman (1)

Abstract

Aneuploidy is the condition in which a cell has extra or missing
chromosomes, and is often associated with tumours. But whether it is a
cause or a consequence of cancer remains a vexed question.
Aneuploid cancers are like Tolstoy’s unhappy families: each aneuploid
cancer has its own particular abnormal chromosome content, and thus
its own abnormal characteristics. This variability has long frustrated
biologists trying to establish whether aneuploidy is a cause or a
consequence of malignant transformation.

1.David Pellman is at the Dana-Farber Cancer Institute, Children’s
Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Email: david_pellman@dfci.harvard.edu

URL: http://www.ncbi.nlm.nih.gov/pubmed/10687734

Curr Opin Oncol. 2000 Jan;12(1):82-8.
Aneuploidy and cancer.
Sen S.

SourceUniversity of Texas, M.D. Anderson Cancer Center, Department of
Laboratory Medicine, Houston 77030, USA. ssen@mdanderson.org

Abstract

Numeric aberrations in chromosomes, referred to as aneuploidy, is
commonly observed in human cancer. Whether aneuploidy is a cause or
consequence of cancer has long been debated. Three lines of evidence
now make a compelling case for aneuploidy being a discrete chromosome
mutation event that contributes to malignant transformation and
progression process. First, precise assay of chromosome aneuploidy in
several primary tumors with in situ hybridization and comparative
genomic hybridization techniques have revealed that specific
chromosome aneusomies correlate with distinct tumor phenotypes.
Second, aneuploid tumor cell lines and in vitro transformed rodent
cells have been reported to display an elevated rate of chromosome
instability, thereby indicating that aneuploidy is a dynamic
chromosome mutation event associated with transformation of cells.
Third, and most important, a number of mitotic genes regulating
chromosome segregation have been found mutated in human cancer cells,
implicating such mutations in induction of aneuploidy in tumors. Some
of these gene mutations, possibly allowing unequal segregations of
chromosomes, also cause tumorigenic transformation of cells in vitro.
In this review, the recent publications investigating aneuploidy in
human cancers, rate of chromosome instability in aneuploidy tumor
cells, and genes implicated in regulating chromosome segregation found
mutated in cancer cells are discussed.
PMID:10687734[PubMed - indexed for MEDLINE] Publication Types, MeSH
TermsPublication TypesResearch Support, Non-U.S. Gov’tResearch
Support, U.S. Gov’t, P.H.S.ReviewMeSH TermsAneuploidy*Cell
Transformation, Neoplastic*HumansMitosisNeoplasms/
genetics*PhenotypePoint Mutation

I seem to recall reading a theoretical article a few years ago that
suggested the use of zinc-finger based logic to detect double deletions
of critical regulatory genes. The premise was that, even without
aneuploidy, many cancer cells will have deleted both alleles of a
critical regulator or two along the way, and detecting these deletions
would permit pretty selective destruction of cancer cells.

The system involved a time-delayed toxin that was inhibited by an
antitoxin. The antitoxin was a split protein conjugated to ubiquitins
and one of two zinc fingers; if the zinc fingers bound adjecent to one
another on an allele, ubiquitin ligase would (theoritically, mind)
ligate the two chimeric proteins, and the reconstituted antitoxin would
protect the cell from death. Clever, but I've not seen it implemented. I
also felt it overcomplicated the first implementation of a fantastic
idea; zinc-finger-mediated protein conjugation by ubiquitin ligase.

By the way, although mature sperm are haploid, the precursor cells
aren't; permanent infertility shouldn't result from a system that
attacks aneuploid cells. Mature eggs are diploid as far as I know, only
"kicking" the second chromosome set upon fertilisation. I may be under a
misapprehension there, though; anyone with more knowledge care to comment?

-- 
www.indiebiotech.com
twitter.com/onetruecathal
joindiaspora.com/u/cathalgarvey
PGP Public Key: http://bit.ly/CathalGKey

> 
> By the way, although mature sperm are haploid, the precursor cells
> aren't; permanent infertility shouldn't result from a system that
> attacks aneuploid cells. Mature eggs are diploid as far as I know, only
> "kicking" the second chromosome set upon fertilisation. I may be under a
> misapprehension there, though; anyone with more knowledge care to comment?
> 

I believe it to be the case. However, megakaryocytes are polyploid all
along. Killing all megakaryocytes would lead to death by haemorrage 
within a week or so.
As mentionned previously, dividing cells would pass through various
apparent states of aneuploidy, too, so there would have to be a way to
avoid killing them.
Lastly, chromosomic superstructures (like telomeres and centromeres, 
which would be the most obvious recognised features) are already used
for other functions (mainly regulation of the cell cycle, senescence
and apoptosis, but probably also as-yet-udiscovered roles). That is, 
for example, what prevent cells from undergoing division if they do 
not have 2 sets of chromatids (well, meiosis excepted). Or what 
triggers senescence. As stated upper in the thread, ploidy is already
one of the most tightly regulated feature in mammalian cells, so 
probably not the target of choice as any "sensor" system would have 
to not disrupt existing interactions. 
Tricky, and potentially very dangerous.
Sensing the deletion of specific antiocogenes or the duplication of
protooncogenes as you suggest would probably be safer.

-- 
PiLS

On Nov 15, 2:59 am, Cathal Garvey <cathalgar...@gmail.com> wrote:
> I seem to recall reading a theoretical article a few years ago that
> suggested the use of zinc-finger based logic to detect double deletions
> of critical regulatory genes. The premise was that, even without
> aneuploidy, many cancer cells will have deleted both alleles of a
> critical regulator or two along the way, and detecting these deletions
> would permit pretty selective destruction of cancer cells.
>
> The system involved a time-delayed toxin that was inhibited by an
> antitoxin. The antitoxin was a split protein conjugated to ubiquitins
> and one of two zinc fingers; if the zinc fingers bound adjecent to one
> another on an allele, ubiquitin ligase would (theoritically, mind)
> ligate the two chimeric proteins, and the reconstituted antitoxin would
> protect the cell from death. Clever, but I've not seen it implemented. I
> also felt it overcomplicated the first implementation of a fantastic
> idea; zinc-finger-mediated protein conjugation by ubiquitin ligase.
>
> By the way, although mature sperm are haploid, the precursor cells
> aren't; permanent infertility shouldn't result from a system that
> attacks aneuploid cells. Mature eggs are diploid as far as I know, only
> "kicking" the second chromosome set upon fertilisation. I may be under a
> misapprehension there, though; anyone with more knowledge care to comment?
>
> --www.indiebiotech.com
> twitter.com/onetruecathal
> joindiaspora.com/u/cathalgarvey
> PGP Public Key:http://bit.ly/CathalGKey


See this press release from MIT

http://web.mit.edu/newsoffice/2011/cancer-detection-circuit-0902.html

for a reported implementation of a logic circuit.

Sincerely,

John