
Cancer Isn’t a Logic Problem - dnetesn
http://cancer.nautil.us/article/186/cancer-isnt-a-logic-problem
======
hprotagonist
This is a special case of the "Andy Grove Fallacy":
[http://blogs.sciencemag.org/pipeline/archives/2007/11/06/and...](http://blogs.sciencemag.org/pipeline/archives/2007/11/06/andy_grove_rich_famous_smart_and_wrong)

> Andy Grove has had prostate cancer, and now suffers from Parkinson’s, so
> it’s no wonder that he’s taken aback at how poorly we understand each of
> those diseases – not to mention all the rest of them. But his experience in
> the technology world has warped his worldview. We are not suffering from a
> lack of urgency over here – talk to anyone who’s working for a small company
> shoveling its cash into the furnace quarter by quarter, or for a large one
> watching its most lucrative patents inexorably melt away. And we don’t
> suffer from a lack of hard-charging modern management techniques, that’s for
> sure.

What we suffer from is working on some of the hardest scientific problems in
the history of the species.

~~~
kumarski
I love Derek Lowe's writing.

------
bobdole1234
Once you build a system that builds treatments for specific problems, you
treat the problem and repeat as they come up.

Not dying of the first cancer is better than dying of the first.

Just because there are N cancers in the series doesn't mean the problem is
impossible, it just means we haven't ever gotten past the first levels to
figure out how it works.

The secret to winning pacman isn't 256 separate strategies, it's a small set
of strategies that fit together once you know how the game changes level to
level.

The author is just fixated on the fact they finished the first level AND THE
WAS ANOTHER!

------
dkarapetyan
> Cancer relates to our fundamental constitution as multicellular organisms,
> our limited lifespan, the epidemiology of the aging population,
> socioeconomics and the future of society.

This is the most important part. Life is cancerous. When people claim to cure
cancer it's sort of an oxymoron. There are indeed no such things as cancer
genes but more like a breakdown in the cooperative biochemical networks that
make multi-cellular life possible. It's actually a great wonder how all those
cells in your body manage to cooperate at all without stepping on each others'
toes all the time.

In a way the delicate balance is a constant fight against entropy and entropy
always wins. Enough breakdowns and misunderstandings in the biochemical
networks and the multi-cellular ecology and you have cancer.

~~~
thaumasiotes
> When people claim to cure cancer it's sort of an oxymoron. There are indeed
> no such things as cancer genes but more like a breakdown in the cooperative
> biochemical networks that make multi-cellular life possible.

This description fits scurvy fairly precisely. But no one would say it's
nonsense to talk about "curing" scurvy. Give someone some vitamin C, and their
scurvy will be cured.

Would you also say it's an oxymoron to talk about "fixing" software bugs
because the terminology assumed they were designed in?

~~~
dkarapetyan
If you look at how cells work on the micro-scale it looks a lot like cancer.
They constantly divide and try to proliferate by allocating and using
resources. The only thing keeping them in check is basically the "cellular
honor code". You can certainly try to make it less likely any given set of
cells breaks the honor code but you can't "cure" cancer. It's an inherent
property of multi-cellular life. Not unlike bee and ant colonies. There is
always one queen (or several) but sometimes there will be a rogue queen born
that bifurcates the colony. Bees and ants go to great lengths to avoid these
situations but the way colonies are set up and structured rogue queens are an
unavoidable part of the colony given a long enough timeline.

I characterize scurvy as a sub-optimal stable operating state where optimality
can be restored. Cancer does not have similar characterization. It's more like
an unstable runaway loop.

But I'm neither a biologist nor a doctor. My understanding is basically a
bunch of analogies between game theory and general systems in the context of
biology and maybe that's not the proper set of analogies for the problem at
hand. In that context cancer is the breakdown of feedback loops that keep the
system stable.

~~~
thaumasiotes
> I characterize scurvy as a sub-optimal stable operating state where
> optimality can be restored.

This makes no sense. It's not a stable operating state. Vitamin C is necessary
to hold your cells together. Scurvy is the failure path of not having vitamin
C; it is a transition from "healthy" to "dead".

> cancer is the breakdown of feedback loops that keep the system stable

OK, but this is _exactly what scurvy is_. They're just different feedback
loops. Infection by foreign bodies is _also_ "the breakdown of feedback loops
that keep the system stable". Your objection applies to everything, which
makes it completely meaningless when you apply it to cancer specifically.

~~~
obstinate
This whole conversation reminds me of
[http://lesswrong.com/lw/iv/the_futility_of_emergence/](http://lesswrong.com/lw/iv/the_futility_of_emergence/).
Claims like "breakdown of feedback loops that keep the system stable" are
basically just a long way of saying, "for reasons I don't understand." All
things happen for reasons, and if it's on the bleeding edge of human
understanding, or beyond current science, it'll likely be for reasons you
don't understand. That does not mean that no entity will ever be able to
understand.

It's a little frustrating honestly. Don't people see that most things seem
impossible until they aren't? Just two years ago a lot of people were quite
confident that computers would never surpass humans at Go.
[https://www.reddit.com/r/baduk/comments/2wgukb/why_do_people...](https://www.reddit.com/r/baduk/comments/2wgukb/why_do_people_say_that_computer_go_will_never/)
This is one of dozens of such links you could find from that period. Much
moreso ten years ago. I get that cancer is a horse of a different color, but
come on. If you are confident that ANYTHING will be impossible in 200 years,
besides things which are physically so . . . well, I just cannot agree.

~~~
dkarapetyan
Stable/unstable/negative/positive feedback loops are technical terms in
control theory
([https://en.wikipedia.org/wiki/Negative_feedback](https://en.wikipedia.org/wiki/Negative_feedback)).
I'm using those terms for specific reasons. I don't quite see what you're
objecting too. Studying biology in the context of systems and control theory
is a pretty well-trodden path
([https://simple.wikipedia.org/wiki/Krebs_cycle](https://simple.wikipedia.org/wiki/Krebs_cycle)).
Much of modern pharmaceutical research is actually about uncovering the
chemical governing loops (another technical term) and affecting them to
achieve positive outcomes.

Cell division is an unstable positive loop that requires dampening with
negative feedback loops at higher organization levels. When those negative
feedback loops break down you get an unstable positive loop in the form of
cancer.

So you see how having cell division in a multi-cellular context can not be
"cured" of cancer? You'd need to stop cell division and somehow figure out a
way around entropy. Cells divide to renew/reset and shed accumulated
environmental damage. So no matter what you do as long as you have a system
organized around unstable processes like this you will always have a control
problem when the negative control mechanisms stop working.

~~~
thaumasiotes
As I've already pointed out to you, every biological system is a feedback loop
in the sense you describe. Feedback loops are how you defecate, how you blink,
how you move, and how you choose how much of what to consume. Feedback loops
regulate the activity of your immune system and seal the holes in your skin
when it's punctured. This doesn't distinguish cancer from anything else.

------
esahione
Erm. This is a terrible argument.

The universe is logical. Each cell in the human body is at its core just a
very complex state machine.

What we call cancer is just a particular state for a cell, and its
descendents.

Find a way to change the cell state, we end cancer. And we know we can change
a cell state-we can transform skin cells into stem cells, so what would make
it impossible to turn cancerous cells into non-cancerous cells?

We just haven't found out the proper way to do so. It takes data, and
simulation, and lots of time. At some point we'll figure it out.

I think the only misguided attempts are chemotherapy-based - damaging cells
indiscriminately, just because cancer cells multiply faster and thus
accumulate dna damage faster and thus die faster than normal cells. This means
that unless you kill all the cancerous cells your cancer will come back. The
problem is chemotherapy drugs will also be damaging your body in other ways,
depressing your immune system, and thus making it easier for any remaining
cancerous cell to start it all over again.

I believe it's much easier to simply figure out the right cocktail that would
change cancerous cells into normal cells again, and then find the delivery
mechanism for that.

I can see a future where we can transform cancerous cells into cancer-killing
cells (let's say T/B Cells) that would just cascade into the complete
eradication of cancerous cells within an organism.

This guy's argument boils down to lack of imagination.

~~~
Palomides
cancer isn't a particular state, except in the vaguest sense of 'continually
multiplying, but like, in a bad way'.

any person's cancer is millions/billions of semi-independent, extremely
complicated, poorly understood state machines, with a variety of mutations,
constantly interacting and evolving against any treatments applied and immune
reactions.

imho, cancer is a fundamental disease/property of multicellular life, and
trivial reductionist perspectives completely out of touch.

~~~
abecedarius
In principle it shouldn't matter that cancer is not well defined, if health is
well defined. "Just" visit every single cell and repair its gene sequence to
your body's consensus sequence, and similarly for the epigenetic state to the
extent necessary -- the latter requires more knowledge to do correctly, but
otoh seems less crucial.

This is of course ridiculously ambitious compared to the current state of the
art, but I think it's a reasonable start to countering the claim that a
general cure for cancer is impossible _in principle_.

~~~
Palomides
A cell /is/ epigenetic state, and the effect of any piece of DNA is profoundly
controlled by other pieces of DNA, RNA, proteins, RNAs interacting with RNAs,
RNAs interacting with proteins, proteins interacting with proteins, etc.
Scrubbing the proteins, RNA, and so forth from a cell without killing it is
inconceivable.

That said, I don't want to say that cancer is fundamentally beyond us. I think
cheap sequencing and emerging highly targeted DNA editing systems, along with
better understanding of the immune response to cancer, will get us most of the
way there in a practical sense.

~~~
abecedarius
Repairs of all these things are performed by the cell itself without killing
itself, so they're surely physically possible. But they're limited by a lack
of outside information -- e.g. if the DNA is too corrupt, the repair processes
can't check the uncorrupted DNA of other cells. That could be fixed with
advanced enough technology.

~~~
Palomides
killing the cell is actually not a big deal, any given cell is generally
replaceable.

What you suggest is more or less what I mention; you could, say, try to add
back some genetic machinery for the cancer cells to recognize that they're
defective, and then they kill themselves. Or help the higher level repair
mechanism (the immune system) target cancer cells.

To my understanding, trying to fix anything at the level between whole cell
and DNA mutation is much harder.

~~~
abecedarius
Yes, I'm not gonna pretend to know what avenues are promising or how long
it'll take to invent -- maybe humans will go extinct or obsolete first. I just
disagree with the article's pooh-poohing towards "why don't we include in our
portfolio of bets some actually trying for a cure someday".

------
nabla9
Gene Regulatory Network resembles (stochastic) recurrent neural network and is
sometimes modeled as such. Each cell has it's own GRN and then there is
signaling between the cells.

Its understandably very hard problem to nudge network states back to the
normal or to kill itself once it's gone haywire and causes other networks go
haywire too. The "error state" cells are changing and those who survive the
last nudge continue to reproduce.

If I understand Kozubek's argument correctly, cancer is ecologic, not systemic
because of this evolution of cancer cell populations. If the cancer is
ecologic problem, solving cancer means that it's not enough to figure out
cell's state and fix it. You must figure out how the cancer cell ecology works
and find a way to drive it into extinction without survivals. Just setting
more mousetraps is not working solution if the mouse population is evolving
hour by hour and branching.

~~~
dwaltrip
This doesn't mean the problem can't be solved by "logic". If true, then
research groups that are operating within such misguided frameworks will need
to update their understanding of how cancer works.

I think a common trope is to point out some system that humans are currently
unable to model in a robust or effective manner, and then throw up one's hands
and declare "science and logic can't be used to solve this problem!" The
current lack of an effective model for some system in no way implies that one
will not eventually be found.

To be fair, this article isn't quite doing that, and makes some very important
points. I only bring this up as it is a misleading line of argument to watch
out for that I run into from time to time, and a few lines in the article were
slightly reminiscent of such reasoning.

Ecology is a scientific endeavor, and perhaps it will prove to be a more
powerful paradigm for looking at a cancer. I hope we can make the most of any
tools at our disposal to significantly reduce the harm caused by cancer.

~~~
nabla9
>This doesn't mean the problem can't be solved by "logic".

That's not what the author was saying.

It's useless to judge articles based on their title or headline because they
are either selected by editor or there are multiple titles and A/B testing is
used to find one that gets most clicks.

It seems that most comments are just comments based on the headline.

~~~
dwaltrip
My comment was mainly a tangent off of yours. It seems I tend to do that... I
should make an effort to make that more clear.

I will say, however, that only responding to my first sentence is sort of like
only discussing the headline :)

------
xherberta
The author's last word:

 _we need to consider that the system of cancer goes far beyond the
biochemistry of cancer cells. Cancer relates to our fundamental constitution
as multicellular organisms, our limited lifespan, the epidemiology of the
aging population, socioeconomics and the future of society. Those who believe
that the problem of cancer can be solved by killing or reprogramming cancer
cells need to take a step back from the molecular technicalities and take a
look at the bigger picture._

~~~
jessriedel
How cancer fits into the evolutionary context is obviously important to
understand, but the author's conclusion is unfounded. Cancer rates in the
ancestral environment is set by a balance between costs and benefits of anti-
cancer mechanism. But we are not in the ancestral environment, and there's no
_a priori_ reason (Darwinian, thermodynamic, or otherwise) to think that
cancer rates couldn't be driven down to negligible rates given our much
greater resources.

------
JabavuAdams
I think I understand the author's point, but just as people here are making
sweeping statements about biology, he seems to have some minor misconceptions
about technology.

Let's take a step back ... my understanding of what the author's saying is
that "solving" cancer is no easier in some sense than "solving" biology.

Yes, we have to think of cancer as some kind of adversarial game -- it's not
enough to solve a snap-shot of that game. But ... that doesn't mean that we
can't have active defences that work for the vast majority of people. It's
just that maybe we need to know how to build people from molecules, first.

I think we'll solve biology in the sense of being able to engineer life from
first-principles. I make no predictions on time-frame.

------
kumarski
There’s ~ 15K-20K diseases that we’ve classified.

There’s 3.2Bn genetic base pairs.

There’s just over 7Bn people.

Maybe like 7M-20M people suffer from a disease or even well below or above
that.

Finding someone at a given time in the exact modality that would be testable
by a given trial is really hard.

Genes are sets of base pairs.

A lot of drug discovery is a situation where you have to test compounds
empirically against a notion of a theory of a viable drug target.

Some drugs may be efficacious, but they may kill you.

Some genes may work in coalition with other genes, not at all, or against some
genes.

There's also the fundamental notion about the druggability of a disease. This
article does a great job in outlining it:
[http://omicsomics.blogspot.com/2017/03/targets-
drugability-r...](http://omicsomics.blogspot.com/2017/03/targets-drugability-
revisited.html)

There are no monstrously hard computational power problems in drug development
that are waiting for mathematical brains to pursue. There are hard Empirical
problems. Empirical problems are problems which require actual experiments to
show resultant data.

~~~
letitgo12345
> There are no monstrously hard computational power problems in drug
> development that are waiting for mathematical brains to pursue

Not sure if I would put it that way. For ex, in principle, you could use
molecular dynamics and search to find protein sequences that form other
proteins/antibodies that can hit targets you want or operate in a more complex
fashion. So hard computational power can most definitely help out (and
depending on level of advance, help out a great deal). Ofc that doesn't mean
you don't need experiments at all.

------
dmritard96
My understanding of this argument is that because of cancers many and possibly
infinite forms there is no 'cure for cancer'. While I can appreciate the
mathematical correctness of this point (sure did take a long article to get
this across), it seems largely to miss the point. If cancer rates become low
enough that they only kick in at 120 and that people begin dying of other
things, whether a small group of people continue to die of cancer vs the rates
today is effectively curing cancer, even if its not entirely complete.

Another example of why this sort of thinking is missing the bigger picture -
many people today die not because we don't know how to treat something, but
instead because they can't afford the treatment.

------
Ericson2314
This is a fine argument articulated quite poorly.

A) cancer cells constitute a separate species, or at least evolutionary
"actor".

B) the tech naivity is not that things can't be deeply understood, but that
it's a moving target, and less than complete erradication of the parasite just
increases evolutionary pressure leading to _decreased_ understanding of the
foe.

------
elihu
I'm not sure what the point of this essay is supposed to be. Should we ignore
promising avenues of cancer treatment research just because they won't work in
all cases or for all cancers, or because the person cured is just going to die
of something else later?

------
glbrew
I strongly disagree with this essay.

------
Eric_WVGG
this bit from PhD Comics, on the same topic, is a classic

[http://www.phdcomics.com/comics/archive.php?comicid=1162](http://www.phdcomics.com/comics/archive.php?comicid=1162)

------
greenhatman
Everything is a logic problem.

~~~
goatlover
Then there is no need for science. The Greeks should had this figured out
millennia ago.

~~~
dwaltrip
Is science not a logical endeavor?

~~~
goatlover
Science an empirical endeavor. The world determines what is, not logic, or
math. Logic and math are great tools for making sense of observations, but
they do not determine what will be observed. Otherwise, there would have been
no need to carry out experiments. People, armed with only logic, could have
deduced any truths about the world from their arm chairs.

Some, like Aristotle, did try to do that. To be fair, it was a mix of
observation and first principles, but it was lacking adequate experimentation,
as humans later found out.

~~~
dwaltrip
> People, armed with only logic, could have deduced any truths about the world
> from their arm chairs.

Fair enough. I'm probably giving too much of my own spin to the word "logic".

I'm thinking of logic as being somewhat grounded in empirical observations. I
agree that armchair logic completely removed from reality is of questionable
value.

At this stage of my understanding, I would argue that our notion of logic and
math largely stems from us creating models about the world that lead to
abstract deductions, which often are eventually used in new models about the
world... and so on. This cycle probably got started as early humans acquired
better mental models for categorizing objects of different types and their
apparent boundaries, and then began to "count" like entities.

If math wasn't useful for describing the world, I doubt we would have done
much with it.

------
reasonattlm
Cancer, like aging, is an example where much of the research community is
undertaking very challenging and expensive work with marginal expectation
value because that dovetails well with the types of fundamental research that
can be funded, not because of any expectation that it is the best approach
with the highest expectation value. This is an age of genetics, genetics is
popular, and so people are getting funded for personalized medicine and ever
more intricate mapping of cellular biology.

But there are hundreds of types of cancer, and taking the genetics/drug
discovery approach for each of them is its own distinct and massively
expensive undertaking. It'll never get done: the research community and its
funding sources are not large enough to make significant progress on the whole
of the problem in the next few decades. This isn't hacking cancer, this is
hacking the cancer funding institutions in order to obtain funding to get on
with the fundamental life science research goal of mapping all of cellular
metabolism. Cancer is the excuse, but not the goal.

This is a cultural problem.

Hacking cancer would be to sit down and say, ok, the economics of this are not
working, we need to find common points to target, a way to produce a universal
cancer therapy at no greater expense than one of these single cancer
therapies.

Some immunotherapies, like CAR-T approaches, are a small step in this
direction, something that can be applied to multiple cancers with a lower cost
of customization per cancer type.

The best target, however, is to block telomere lengthening; disabling both
telomerase and alternative lengthening of telomere (ALT) mechanisms. This is a
small area of biochemistry in comparison to the scope of most single cancer
explorations. All cancers depend on telomerase or ALT or both. All of them. No
exceptions. No cancer can evolve its way around a suppression of these
mechanisms. It will simply die, losing its ability to replicate
uncontrollably. Some noted research groups are making early inroads into
disabling telomerase in a targeted way. ALT remains to be dealt with, but is
easier to work with than telomerase interdiction by virtue of the fact that
ALT doesn't happen in normal cells.

A telomere lengthening interdiction treatment would be applicable to all
cancers, and it doesn't appear to be more expensive to develop than any other
approach to a specific cancer. That is what hacking cancer research looks
like; identifying a way to completely change the economics of the situation,
and redirect the primary effort back to producing an effective cures as soon
as possible.

Lastly, I have to fundamentally disagree with the final lines of this article;
cancer can absolutely be dealt with robustly by killing cancer cells. You just
need to be selective enough, early enough, and comprehensive enough, and
raising the bar on these items is the whole point of the field.

