
Why haven't we cured cancer yet? - vibrunazo
http://www.sciencebasedmedicine.org/index.php/personalized-medicine-vs-evolution/
======
Retric
This is one of the most fascinating and frightening things I have ever read.
It really feels like staring cthulhu in the face.

TLDR: _Breast cancers, for instance, have been shown to harbor at least 1,700
different mutations, but only three of them showed up in at least 10% of
patients, with the great majority of them being unique to each patient. The
most recent study in Nature discussed above shows that even a single subtype
of breast cancer that is generally treated clinically more or less the same,
TNBC, varies wildly (and almost continuously) in the genomic changes and
mutations each tumor has. Not only that, but each TNBC is in essence several
diseases, because each TNBC is made up of many different clones that have
evolved as the tumor itself grew, progressed, and evolved. All of this occurs
even before the tumor has been subjected to any treatment at all. As if that’s
not bad enough, it would appear that tumors are a mosaic of groups of many
different tumor cell types that develop through branching evolution such that
metastases can be very different from the primary tumor and even different
regions of the primary tumor can be very different from each other, so much so
that finding a “favorable prognosis signature” on a core biopsy means only
that that one area biopsied has that gene signature. Large areas elsewhere in
the tumor could have the unfavorable prognosis signature._

And even more interesting if you look at the history of a tumor the mutations
goes back for a fairly long time, possibly on the order of 30+ years. While it
may not be an actual cure, removing abnormal cells early may be more effective
than trying to treat cancer in the last 1-10% of it's lifetime when it's
already become a diversified killing machine.

~~~
micro_cam
All this genetic diversity seems daunting at first but I think it is also
indicative of something that gives me great hope.

Cancer isn't like a virus or pathogen that has evolved to avoid it our immune
systems and treatments as it passes from individual. It is a degenerative
state of the same system that produces healthy cells and fertile humans.

It is genetically very diverse. Part of this is because cancers cells often
have mesed up chromosomal replication which produces more variability. Part of
this may be because numerous genetic variations can have similar effects
because they effect the same gene or network of genes.

As the author alludes to at the end of the paper, there are a number of things
a tumor must do to be successful. These include avoiding the immune system,
avoiding programed cell death, recruiting blood vessels/nutrients etc. There
has been lots of really promising research in the last few years that looks at
analyzing and targeting the pathways that control these things.

Further as projects like the the Cancer Genome Atlas (which I work on as a
Software Engineer) produce terabytes of data about cancer, we are able to
apply modern data analysis to better understand the system, hopefully
discovering what separates the biochemical state of an aggressive cancer from
one the body handles without issue which will hopefully lead to some novel
drug targets.

~~~
jimmyvanhalen
Here's something interesting about a common chemical compound called
Dichloroacetic acid (DCA). Big pharma is ignoring it since it can't be
patented (because it's so common).

 _Cancer cells change the way they metabolize oxygen in a way that promotes
their survival. In laboratory studies of isolated cancer cells grown in tissue
culture, DCA restores the original metabolism, and promotes their self-
destruction. This has led to the use of DCA for treating cancer, by
individuals experimenting with it themselves, by doctors administering it to
patients as a non-approved drug, by scientists testing it in cancer tissue
cultures in cell culture and in mice, and in human Phase II studies. DCA has
improved certain biochemical parameters, but it has not demonstrated improved
survival.

Cancer cells generally express increased glycolysis, because they rely on
anaerobic respiration that occurs in the cytosol (lactic acid fermentation)
rather than oxidative phosphorylation in the mitochondria for energy (the
Warburg effect), as a result of hypoxia that exists in tumors and
malfunctioning mitochondria. [9] [10] Usually dangerously damaged cells kill
themselves via apoptosis, a mechanism of self-destruction that involves
mitochondria, but this mechanism fails in cancer cells. A phase I study
published in January 2007 by researchers at the University of Alberta, who had
tested DCA on human[11] cancer cells grown in mice, found that DCA restored
mitochondrial function, thus restoring apoptosis, allowing cancer cells to
self-destruct and shrink the tumor.[12] These results received extensive media
attention, beginning with an article in New Scientist titled "Cheap, ‘safe’
drug kills most cancers".[11] Subsequently, the American Cancer Society and
other medical organizations have received a large volume of public interest
and questions regarding DCA.[13] Clinical trials in humans with cancer have
not been conducted in the USA and are not yet final in Canada, emphasizing the
need for caution in interpreting the preliminary results.[13][14]_

<http://en.wikipedia.org/wiki/Dichloroacetic_acid>

~~~
refurb
Big pharma isn't ignoring it because of the patent issue, they are ignoring it
because it doesn't work that well.

They may not be able to get a "composition of matter" patent on it, but they
could get a "use" patent on it.

For a great example of a VERY common chemical that big pharma is developing,
check out BG-12 from Biogen. It's dimethyl fumarate, something you can buy in
ton quantities and most labs have jars of it. They are developing it for MS
and it looks quite promising.

[http://www.drugs.com/clinical_trials/oral-bg-12-dimethyl-
fum...](http://www.drugs.com/clinical_trials/oral-bg-12-dimethyl-fumarate-
significantly-reduced-multiple-sclerosis-ms-relapses-disability-12528.html)

~~~
jimmyvanhalen
They don't know DCA doesn't work that well because they are not spending money
on R&D.

I agree they can get a use patent on DCA, as a matter of fact the researcher
from University of Alberta already has a use patent on DCA as a cure for
cancer.

interesting info on BG-12. thanks.

~~~
refurb
Big drug companies are CONSTANTLY exploring new areas, trust me, they looked
into DCA and found it wanting.

I can't personally attest to the amount of R&D dollars spent by pharma on R&D,
but it has been EXTENSIVELY studied, just checked out pubmed (gov't funded
research).

<http://www.ncbi.nlm.nih.gov/pubmed?term=dichloroacetate>

If DCA were an effective agent, they would have handed the U of A a handsome
check for that use patent. They didn't, so what does that tell you?

~~~
kamjam
I have a question. There are loads of cancer charities, such as Cancer
Research UK, . Does donating to these make any difference in progressing the
research for a cure/treatement or does it not make any serious dent compared
to the big pharmas?

~~~
polyfractal
Yeah, it does. But mostly because big pharma's actual "research" is pretty
slim. Most basic research is done by university professors and their labs,
which are then sold, licensed or simply picked up by big pharma.

Basically, big pharma doesn't have much time or money to spend on basic
research since it has to run clinical trials and make money.

------
elchief
We haven't cured a lot of things. Well, we've cured lots of small things, but
few of the doozies.

A baldness cure has been ten years away for the last thirty years. No cure for
blindness, AIDS, lost limbs. Remember the blue denim dye that killed cancer?
What happened to it?

If something is "ten years away", it means we simply don't know how to do it,
we are just hoping for someone else to come up with the tech to solve it for
us. Even if it's "five years away", it's suspect. Why not just release it now?
Oh, because it doesn't work. I'll believe something if it's being currently
tested on monkeys.

We simply don't have the technology yet to solve these problems. These
problems won't likely be solved in medicine, but in another field that
discovers the solution accidentally, likely in nano or AI/statistics.

If you want to speed things along, make sure the government is dropping lots
of coin in R&D in many NEW or PROMISING fields, not just medicine. Encourage
intellectual property rights for innovative firms that do real R&D, and not
just relabel their old products. Encourage your smart friend to go into bio-
stats and not quantitative finance.

~~~
Retric
Most of the big things we cured where diseases that no-longer seem to be a big
deal because they where cured. Food born illness, measles, and smallpox are
all things that have killed more people than AIDS and are no longer a problem
in the western world.

Measles what's that? _If vaccinations were stopped, each year about 2.7
million measles deaths worldwide could be expected._
<http://www.cdc.gov/vaccines/vac-gen/whatifstop.htm>

And "Smallpox is believed to have emerged in human populations about 10,000
BC... Smallpox was responsible for an estimated 300–500 million deaths during
the 20th century" <http://en.wikipedia.org/wiki/Smallpox> We are talking about
something that killed around A BILLION PEOPLE and now it's 'gone'.

At it's current rate AIDS might catch up to Smallpox 200-600 years from now.
But, that's just deaths the side effects where far more common. She might not
be dead but I don't like seeing this picture.
[http://en.wikipedia.org/wiki/File:Child_with_Smallpox_Bangla...](http://en.wikipedia.org/wiki/File:Child_with_Smallpox_Bangladesh.jpg)

PS: You say there is no cure for blindness, but smallpox was responsible for
1/3 of all blindness cases which just don't happen any more.

~~~
web_chops
Actually creating most of the viral vaccines is more like theming a computer
interface, you just need to plugin the new virus into your already well
defined research work flow. That's the only reason we even have so many
vaccines for so many viruses (even considering mutations and unknown strains).

Drop in one virus (AIDS, H1N1) which is out of the well known workflow and
every thing goes haywire. I think the main reason for this whole mess is that,
out of all the STEM fields, biology is the most trial and error prone.

It's the equivalent of trying to prove a mathematical formula every single
time you want to use it because there are no axioms. Until some one discovers
some standard good for everything axioms in biology, it will continue to be
retarded cousin of all STEM fields.

------
Dn_Ab
What I got from this:

\- Cancer is complex, its profile is not that of 1 disease but many hundreds
of diseases

\- Sequencing Cancers and attempting to find a match to suggest a treatment
will not work, each cancer is unique and itself made up of a diverse
population

\- Cancer is mutiny combined with the greed of evil dictators. A bunch of
cells give up the chain of command and start co-opting resources to feed their
opulent lifestyles. What this means is that no simple cure is going to work,
cancer effectively exists to solve the problem of maximizing its growth or
survival rate. Treatments are just another constraint that increase the
dimensionality of the cancers' search space.

\- Tumorous cell lines are invaders even if they originate from the body and
evolve at a breakneck pace. This is why many treatments fail to work - not
that the ideas behind them are wrong but the system has outsmarted it. Cancer
is dynamic not static.

I found this inspiring and positive. While some may despair from a lack of a
cure what I see is progress. We've gone from the boundless optimism that comes
from ignorance to the sober determination that comes from an awareness of the
extent of our ignorance. So now maybe the real work can begin.

He says tackling the evolutionary aspect of cancer will be key. I wonder if
game theory will inform future treatments. Or if there will be things people
will take to reduce mutations or lend better error correction - outside immune
and optionally germ cells. Or ubiquity of sensors allowing one to cluster
features which determine the onset of cancer and forming tests to pinpoint and
drugs to eradicate before the cancer stage. I wish I was not so ignorant.

~~~
epistasis
>\- Sequencing Cancers and attempting to find a match to suggest a treatment
will not work, each cancer is unique and itself made up of a diverse
population

It seems to me that sequencing is a must, rather than a "not work," as without
that type of intelligence one can't even know what you're up against. You just
need to take into account the diversity of mutations, and not assume that
you've seen everything that's currently in the population.

~~~
Dn_Ab
You are right. I did not mean that sequencing shouldn't be done, what I meant
was that the simple idea of sequence -> nearest match -> most appropriate
treatment won't work due to the massive amount of variance involved. So the
sequencing will be more useful at higher level. So more understanding patterns
and devising strategies than personalizing cocktails.

~~~
epistasis
Ah, I see what you're saying. Though even going with the best treatment in the
nearest match is a huge leap forward over what we can currently do. I see two
ways forward, using the current class of chemotherapeutics + small
molecule/antibody targetted therapies. As straw men, they are:

1) come up with a totally complete model of what everything in the cell does,
how the mutations affect those interactions amongst gene products, and change
the cell, and then designing some treatment to selectively kill that tumor
population and to also block off obvious avenues to evolve resistance.

2) the "dumb" approach, figure out classes of disease, and try to use
induction from the results of previous patients in that class of disease to
figure out the best treatment for the current patient.

Right now both avenues are being pursued as best as possible. The first straw
man is far from being approachable; we know so little about molecular biology,
and when physics can't even figure out how to fold a protein, how are we going
to be able to figure out changes to protein-protein binding dynamics, etc? Not
that it can't be done eventually, but it's a very tough road.

The second approach is probably the best we can do now, and corresponds very
well to the type of machine learning that is being researched these days. Even
without full understanding of the biological system and the effects of all
possible mutations, we can combine what we currently know with machine
learning to construct a black-box for the parts of molecular biology that we
don't yet know. I think that this is probably the most reasonable path forward
for the time being, though we clearly need some intelligent way to guide
studies into the combinatorial effect of targeted therapies.

~~~
Dn_Ab
I think Moore's law can help to an extent with approach 1, especially the
protein folding bottleneck. We also need better computational techniques,
taking more from dynamical systems maths for example.

I think approach 2 can also inform approach 1. Especially if grey and clearbox
models are used - probabilistic graphical models, markov logic networks even
genetic programming. So instead of using them for just prediction or a
distance metric, we study the patterns in the models they produce. For
example, instead of merely fitting a bunch of weights in some sum product
model, one could use genetic programming where the primitives represented
actual computations from a simplified model of cell dynamics. So while not
guidance it still offers some way of embedding some intelligence in the
search.

------
siculars
... Because PhD's can barely feed themselves.

... Because the "smart" people work on Wall Street/for consulting firms.

... Because Facebook acquired Instagram.

~~~
polyfractal
This needs some more love. Consider the cycle of academic career:

-Grad school for 5-8 years, averaging around 7 for most molecular and cellular biologists. You make $23-28k a year depending on where you live. You steal whatever free food is lying around your department

-Post graduation, you obtain a Post-Doc position for ~2 years (if everything goes well). This pays ~40k/year, again varying depending on region.

-If you got lucky and had a successful Post-doc, skip to the next bullet. Otherwise, go back to the last bullet for another 2-8 years.

-Get a junior professor tenure-track position. Salary is much better, probably around 60-80k. You have five years to prove you are awesome. At five years, go to the next bullet

-Tenure review! How many awesome papers did you publish?

\---Not enough? go try again at a different university...hopefully your family
is willing to relocate or there is one nearby. If you fail tenure review
twice, you get to be an adjunct professor (zero job security, crap salary) for
the rest of your life.

\---Well, you don't completely suck...so we are giving you another two years
to prove tenure. Go back to the last bullet.

\---Wow! You got tenure! Welcome to the elite minority that actually make
tenure. You get a nice salary bump up to 100-150k, have total job security, do
zero science anymore (glorified manager now) and are probably in your 40's.
Feels good, huh?

And people wonder why things are slow in biology? If this was a sales funnel,
you would notice hideous conversion rates between all the steps. People burn
out because of intense competition for few spots, crappy salary and crappy
hours.

If you work finance, you may work 90 hour weeks but at least you make lots of
money. In biology...you work 70 hour weeks for food stamps and the hope of
getting tenure when you are 40.

~~~
alexholehouse
The difference is people rarely go into academic research for money - it's not
just a job, it's a lifestyle choice. If you wanted to do research and receive
better compensation you could work in industry or for a government lab - still
research but less freedom.

~~~
polyfractal
Sure, but the harsh reality of life often gets in the way of your lifestyle
choice.

I've known several post-docs that have a wife and kids...and zero in savings
because they only make $40k a year. Not everyone can afford to continue "doing
what they love" when they have a family to provide for.

A lot of these people leave academic research to take up industry jobs where
they reformulate cholesterol medication or research new ways to cure
allergies.

I personally got out of biology because I enjoy software engineering just as
much, but one compensates so much more in terms of pay. If I was making an
equal salary in biology, there would be a good chance I would still be there
trying to solve the world's problems.

So I suppose that's my point. Not everyone has the willpower, option or
incentive to stay in a field they would otherwise enjoy working in, simply
because of the timescale involved and the meager financial pay.

------
JumpCrisscross
Fascinating paper on returns on cancer research out of the NBER argues that
for about $300 billion in cancer research expenditures from 1988 to 2000 the
US created 23 million life-years worth, in aggregate, about $1.9 trillion [1].
That comes to about a 52% smoothed return. Pretty good given that the S&P 500
grew at about 14.6% over the same period (though if similarly smoothed yielded
about 42%).

[1] <http://www.nber.org/papers/w15574.pdf?new_window=1>

[2]
[http://quicktake.morningstar.com/index/IndexCharts.aspx?Coun...](http://quicktake.morningstar.com/index/IndexCharts.aspx?Country=USA&Symbol=SPX)

~~~
ximeng
Is there some way to make a fund investing in research with returns based on
the effectiveness of the results?

~~~
JumpCrisscross
If you could find a counter-party to enter into a swap with you can base it on
anything. But given that it would be virtually impossible to hedge you would
have the odds severely stacked against.

------
blinkingled
Highly recommended reading on the subject : The Emperor of All Maladies :
Kindle URL - [http://www.amazon.com/Emperor-All-Maladies-
ebook/dp/B003UYUP...](http://www.amazon.com/Emperor-All-Maladies-
ebook/dp/B003UYUP58/ref=sr_1_1_title_1_kin?s=books&ie=UTF8&qid=1333996630&sr=1-1)

------
Rhapso
<rant type="likely-naive"/>

We can never "cure" cancer. We might be able to save most individuals from
dying from it some day but cancer is just a mutation that makes a cell's
behavior damaging/lethal to the host body. The only way to prevent "bad"
mutation (because there is no sure way to discern 'bad' from any other
mutation) is to stop mutation all together, and even if there way a way to do
this (removal of radiation does not stop transcription errors) stopping
mutation is a nice kindly way to ensure the extinction of the species (no
chance for future biological adaptation, because there are no mutations). So,
as evil and painful as cancer is, it is a symptom of a good thing, biological
mutation and variation in our species, and any through and final "cure to all
cancer everywhere" will have to stop the cause of cancer, mutation, which we
as a society and species should not allow.

</rant>

~~~
avgarrison
I disagree that we should not allow such a thing if it existed. I think humans
are a bit past the need for biological evolution. Technology can provide us
with the ability to adapt to new challenges and environments, and can do so
much more quickly.

~~~
aidenn0
Also, plenty of biological evolution can happen in the absence of mutation.

~~~
mindcruzer
I'm not sure why you're being downvoted. Evolution is simply the changing of
allele frequencies over time, which can certainly happen in the absence of
mutation. Although, I don't know that I would say "plenty" of evolution can
happen without mutations, but I guess that depends on what you think "plenty"
is.

~~~
revelation
Only changing allele frequencies is proven to result in a stable state. You
need mutation for evolution.

~~~
mindcruzer
Changing of allele frequencies can occur by creation of new alleles (ie.
mutations), but it doesn't have to. The definition encompasses both
possibilities.

------
alexholehouse
One angle I feel is often missed in the whole cancer discussion is that it's a
multidimensional problem.

1) Developing drugs which can damage cancer cells selectively.

Like selecting a few needles in a haystack, cancer cells typically "look" the
same as healthy cells, which makes selectively destroying them very difficult.
Some cancers (such as CML) have a specific driver mutant proteins which allows
for a pinpoint attack (Gleevec), but if this target protein mutates and
Gleevec can no longer bind then that drug instantly becomes totally
ineffective.

2) Identifying malignant tissue

Surgery is still one of the most important tools against many forms of cancer,
yet being able to identify malignant tissue vs. healthy stuff has always been
a problem. In the first half of the 20th century the radical mastectomy was
all the rage, but in reality provided little benefit. I was lucky enough to
see Roger Tsein speak a few years ago (Nobel prize for GFP) who is pioneering
a way to fluorescent tag malignant tissue which can be viewed in real time to
give surgeons an augmented reality overview of a tumour to maximize the chance
of getting all the malignant
cells.[[http://en.wikipedia.org/wiki/Roger_Y._Tsien#Fluorescence-
ass...](http://en.wikipedia.org/wiki/Roger_Y._Tsien#Fluorescence-
assisted_cancer_surgery)].

3) Stopping metastasis

Even if a patient presents with a tumour and that tumour is removed, it's
impossible to tell if any of the maligant cells have managed to escape to
other parts of the body, where they slowly start to regroup before launching a
subsequent attack. This is the primary reason why cancer survivors have 5Y and
10Y survival rates as opposed to, "You're cured". The mechanism and time in a
cancer at which this happens depends on so many factors its currently almost
impossible the predict.

4) Drug delivery

The tumour micro environment is so foreign compared to the normal stromal
environment, and moreover so heterogeneous between tumour types (which in turn
depends both on a cancer's underlying genotype and its associated tissue,
vascularization and a wide range of additional factors) that creating drugs
which can just _survive_ long enough to act on their target can be difficult.
This, combined with the fact that tumours are, compared to normal tissue,
often poorly vascularized, means just getting drugs in can be a major
challenge. I remember reading how often the vascularization of a tumour can be
proportional to rate of growth and inversely proportional to chemotherapeutic
efficacy (although don't quote me because I can't find the reference) meaning
smaller, slower growing tumours often represent those most difficult to treat
while larger, more aggressive ones may respond better, if caught in time.

5) Cancer is effectively microscale evolution

Perhaps the biggest problem is that once cancer cells begin to acquire some
initial mutations (and lie in a pre-cancerous form) they're often more
susceptible to further mutations. In a way, this allows them to employ a sort
of bet-hedging strategy, such as that seen by yeast or other single celled
organisms. No longer can we treat the cancer cells as part of our
multicellular body, but as a separate, single celled population. This means
that even if certain drugs are effective, there will be a small population of
cancer cells who may have mutated in such a way that they are resistant, so
even if a treatment gets 99% of the cells, that final 1% can restart and the
same bet-hedging strategy is re-employed to create another, diverse set of
cells. This is totally analogous to antibiotic resistance. The range of this
diversity varies significantly between cancers, but as we "pick out" the
easier ones with an obvious target, this will become an every increasing
issue.

These are just a few points - there are more, but I've tried to focus on ones
not yet brought up in discussion. This is an area I have some experience with,
and if anything is unclear let me know and I'll do my best to explain.

[EDIT]: This is not meant to be quite as, "we're all doomed" as it appeared. I
think Dn_Ab's post summarizes how I feel more accurately. The development in a
range of different areas has been staggering (childhood leakemia, CML, Her2+
BC etc), and the reason this is such a daunting task is because the magnitude
has only reared its large, complex head in the last 10-15 years or so. Despite
the challenges, it is a very exciting time to be a cancer biologist.

~~~
moldbug
I'm going to be a heretic and argue that the problem with cancer research is
institutional, not biological. The biological problem is clearly very hard,
but the institutional problem is impossible.

You might or might not be familiar with the term "OODA loop," originally
developed by fighter pilots:

<http://en.wikipedia.org/wiki/OODA_loop>

If the war on cancer was a dogfight, you'd need an order from the President
every time you wanted to adjust your ailerons. Your OODA loop is 10-20 years
long. If you're in an F-16 with Sidewinder missiles, and I'm in a Wright Flyer
with a Colt .45, I'm still going to kill you under these conditions. Cancer is
not (usually) a Wright Flyer with a Colt .45.

Lots of programmers are reading this. Here's an example of what life as a
programmer would be like if you had to work with a 10-year OODA loop. You
write an OS, complete with documentation and test suites, on paper. 10 years
later, the code is finally typed in and you see if the test suites run. If bug
- your OS failed! Restart the loop. I think it's pretty obvious that given
these institutional constraints, we'd still be running CP/M. Oncology is still
running CP/M.

Most cancer researchers are not even _in_ the loop, really. For one thing, 90%
of your research is irreproducible:

[http://www.pharmalot.com/2012/03/many-cancer-studies-are-
act...](http://www.pharmalot.com/2012/03/many-cancer-studies-are-actually-
unreliable/)

Even when the science is reproducible, your cell lines and mouse models are
crap and bear little or no resemblance to real tumors. You know this, of
course. But you keep on banging your heads against the wall.

What would a tight OODA loop look like? Imagine I'm Steve Jobs, with infinite
money, and I have cancer. Everyone's cancer is its own disease (if not
several), so the researchers are fighting one disease (or several), instead of
an infinite family of diseases. They are not trying to cure pancreatic cancer
- they are trying to cure Steveoma.

Second, they operate with no rules. They can find an exploit in Steve's cancer
genome on Wednesday, design a molecule to hack it on Thursday, synthesize it
on Friday and start titrating it into the patient on Saturday.
Pharmacokinetics? Just keep doubling the dose until the patient feels side
effects. Hey, it worked for Alexander Shulgin.

Moreover, Steve isn't on just one drug. He's got thirty or forty teams
attacking every vulnerability, theoretical or practical, that may exist in his
cancer cells. Why shouldn't he be attacking his cancer in 30 ways at the same
time? He's a billionaire, after all.

Not everyone is a billionaire. But if you do this for enough billionaires, the
common elements in the problem will start repeating and the researchers will
learn a repertoire of common hacks. Eventually, the unusual becomes usual -
and cheap. This is the way all technology is developed.

Of course, someone might screw up and a patient might die. You'll note that a
lot of cancer patients die anyway. Steve got a lot, but he didn't get this -
why not? It would be illegal, that's why. Sounds like something the Nazis
would do. Nazis! In our hospitals! Oh noes!

The entire thrust of our medical regulatory system, from the Flexner Report to
today, is the belief that it's better for 1000 patients to die of neglect,
than 1 from quackery. Until this irrational fear of quack medicine is cured,
there will be no real progress in the field.

The entire process we call "drug development" is an attempt to gain six-sigma
confidence that we are not practicing quack medicine. Especially for cancer,
do we need all these sigmas? And are we obtaining them in an efficient way? I
can't imagine how anyone would even begin to argue the point.

What is the source of this phobia? It is ultimately a political fear - based
on public opinion. Its root is in the morbid, irrational fear of poisoning.
But it also has a political constituency - all the people it employs. In that
it has much in common with other "anti-industries," like the software patent
mafia.

~~~
Gatsky
You are ranting about your own confabulated view of cancer research.

Crizotinib is a case in point. It is a small molecule that works very well for
lung cancer, but only if a patient's cancer has a particular chromosomal
fusion. This drug went from being a 'candidate' molecule to having gold
standard data and FDA approval in 5 years. No fantasies about billionaires
required.

The way you conceptualise a cancer patient's plight is also insulting and
grotesque. They are not nihilists willing to try anything, who we can gladly
sacrifice in our pursuit of cure. They have family and friends, and they
really want to go their granddaughter's wedding next month and if you harm
them with loosely justified bullshit science, you haven't helped anyone.

~~~
moldbug
_This drug went from being a 'candidate' molecule to having gold standard data
and FDA approval in 5 years._

Five years! I know that's fast by industry standards. Why, it's only one more
year than it took us to win World War II. Also, for a full measure of the OODA
loop, you should start counting from when the target was discovered.

 _The way you conceptualise a cancer patient's plight is also insulting and
grotesque. They are not nihilists willing to try anything, who we can gladly
sacrifice in our pursuit of cure. They have family and friends, and they
really want to go their granddaughter's wedding next month and if you harm
them with loosely justified bullshit science, you haven't helped anyone._

"Insulting and grotesque" is apparently in the eye of the beholder. I actually
find this attitude pretty insulting and grotesque.

Some patients, it's true, are very comfortable being paternalized. Both my
grandfathers were killed by the present standard of care in prostate cancer,
"watchful waiting." They were both men who would have died rather than
challenge an authority figure. And die they did.

~~~
polyfractal
Honest question: would you be less bitter about your grandfathers' death if
they had been given some unproven, entirely experimental risky drug...and then
died immediately after because of said drug?

How would you feel about your grandparents being used as a few more numbers to
confirm that a drug is not, in fact, effective or safe in treating prostate
cancer?

~~~
moldbug
_Honest question: would you be less bitter about your grandfathers' death if
they had been given some unproven, entirely experimental risky drug...and then
died immediately after because of said drug?_

I'd feel much better about it. Because I know that they'd have been killed in
the front line by a shell - not in the Paris latrines by cholera.

My father's father fought in the Battle of the Bulge. They weren't pussies
back then, you know.

 _How would you feel about your grandparents being used as a few more numbers
to confirm that a drug is not, in fact, effective or safe in treating prostate
cancer?_

Typically when you're trying to "confirm" something it means you think you
know it anyway. No, I don't think any p-value is worth dying for.

Your turn. Honest question: here's a story by a UK woman who jumped for joy to
learn her cancer had spread, because it meant she could get into a trial:

[http://www.telegraph.co.uk/health/9193018/Back-to-work-
after...](http://www.telegraph.co.uk/health/9193018/Back-to-work-after-
radical-cancer-treatment.html)

How do you feel about this situation? Is it by any chance a little too
"Tuskegee" for your sensitive ethical vibrissae?

~~~
polyfractal
No need to get hostile. My girlfriend's mother died from a very aggressive
cancer just last year - I'm well aware of the painful reality of both cancer
and treatment.

Regarding my comment about confirmation, there are always points in any
experiment where you basically know the outcome, but just need a few more
datapoints to pass that magical p < 0.05 number. At that point, they are
technically just killing people and wasting time.

Of course that is a terribly cynical viewpoint. You could easily reword it to
sound much more positive. But I think my original point still stands.

There are always going to cases like the woman's above - it is inevitable. You
can't immediately clear everyone for every drug. Some drugs are _only_
effective when the cancer has progressed to a certain point. But barring
technical problems, there just simply isnt enough money to pay for everyone to
have every experimental treatment.

Triage and thresholding is an unfortunate necessity.

------
jakeonthemove
Very interesting read... it boggles my mind how complex our organisms are and
how cancer forms and takes everything over from the inside.

We can't even "cure" a relatively simple virus like the cold or influenza, and
cancer is like 10,000x times more complicated - gotta respect all the hackers
who're working in the medical field...

~~~
Peaker
Viruses and bacteria evolve much faster than cancer, because they:

* Use horizontal genetic exchange, so different evolutionary branches can share features. This increases evolutionary speed exponentially.

* Evolve over a much larger eco-system, whereas cancer has to evolve "from scratch" in each individual over a relatively short time-span.

Thus, I think cancer should be a _much_ easier problem, from the evolutionary
perspective, than bacteria and viruses.

------
samth
The whole concept of "curing" cancer is silly, and best abandoned. Cancer is
just the name we give to the failure of certain kinds of cell regulatory
systems, particularly those relating to growth and cell death. Coming up with
a "cure" for "cancer" makes no more sense than coming up with a "cure" for
buggy web programs. Just like with web programs, there are certain common
patterns in cancers that can be addressed and mitigated (XSS, estrogen
receptors). But over a long time horizon, all complex systems have failure
modes, and that's all cancer is.

------
Peaker
If p53 is so critical that many cancers disable it, couldn't we genetically
replicate it in our genome many times, to make it far harder for cancer to
disable?

Why didn't this happen naturally, by evolutionary processes?

Is it because all copies of p53 can be disabled simultaneously via RNAi? If
so, maybe particular disablers of p53 can be targeted too?

~~~
alexholehouse
p53 operates as a tetramer (4 individual p53 [monomeric] proteins come
together to form the active protein complex), and can have a dominant negative
effect if one of the two p53 genes are mutated. This basically means we have
two copies of the gene, but if one is mutated and you form a tetramer and 1 or
more of the tetramer's monomers are mutants then that tetramer is far less
active. Even if you had lots of copies of p53, its effect could still be down-
regulated by a single mutant.

There's been some work to try and reactivate p53 where it's been knocked out,
although I'm not sure how successful it's been.
[http://www.ejcancer.info/article/S0959-8049(03)00454-4/abstr...](http://www.ejcancer.info/article/S0959-8049\(03\)00454-4/abstract)

------
donaldc
Given the article talks about decades-long lead times before a cancer
metastasizes, I hope that more attention begins to be focused on much earlier-
stage detection and treatment. I think a lot of the problem is, by the time a
cancer has metastasized and one begins showing _symptoms_ , it's already very
late in the game to try and fix things.

From the article:

 _Moreover, as was discussed in at least a couple of talks at the AACR
meeting, an evolution-based analysis of tumors using the latest NGS techniques
indicates that for most solid tumors the time from founder mutation to
clinically apparent metastasis is between 20 and 30 years. For example, for
pancreatic cancer it’s a median of around 21 years, and for colon cancer it’s
around 30 years._

~~~
jimmyvanhalen
early-stage detection and treatment is critical. I lost love ones to cancer
because the cancer was not diagnosed early enough.

somewhat related to the discussion. saw this last week.

 _Daily Aspirin May Help Prevent and Treat Cancer

“What really jumps out at you in terms of prevention is the striking 75
percent reduction in esophageal cancer and a 40 to 50 percent reduction in
colorectal cancer, which is the most common cancer right now,” Dr. Rothwell
said. “In terms of prevention, anyone with a family history would be sensible
to take aspirin,” he added._

[http://www.nytimes.com/2012/03/21/health/research/studies-
li...](http://www.nytimes.com/2012/03/21/health/research/studies-link-aspirin-
daily-use-to-reduced-cancer-risk.html)

[http://online.wsj.com/article/SB1000142405270230472440457729...](http://online.wsj.com/article/SB10001424052702304724404577295462452273218.html)

[http://www.webmd.com/cancer/news/20120320/daily-aspirin-
may-...](http://www.webmd.com/cancer/news/20120320/daily-aspirin-may-help-
prevent-and-treat-cancer)

------
noonespecial
The National Cancer Institute's average yearly budget for cancer research is
around $4.9 billion. NFL football revenue? $9 billion. Priorities.

~~~
maratd
What's the point of living if you can't have a little fun? Living merely for
the sake of living is pointless.

~~~
noonespecial
Its odd. I was quite curious to float this opinion in this crowd. It is of
course, wildly unpopular among the non-geeks in my "regular" life. I wondered
if it would also be so here. Affirmative.

It always seemed to me that we should "take care of our business" first, and
then play later. To see these numbers backwards (IMHO) struck me as a childish
"play _first_ " attitude. I wouldn't go so far as to say "cancel sports until
we get our health problems sorted out" but a shift in priorities would be
refreshing.

Football is fun, finally cracking our genome to make disease obsolete (and I
think nothing less than 100% of this cures cancer)... now that would be
something to cheer about.

~~~
maratd
> It always seemed to me that we should "take care of our business" first, and
> then play later.

This sentiment only works when the "business" is a low hanging fruit. In other
words, very doable with reasonable effort with results in the short-term.

Anything else, and you hunker down for the long haul. And that means plenty of
playing in the interim. For "business" that can take a lifetime or several
lifetimes, no, you should definitely make sure you play and play vigorously.

Nobody should be asked to sacrifice the quality of their life for the sake of
hypothetical benefits for future generations.

------
hooande
The part that jumped out at me was this: "for most solid tumors the time from
founder mutation to clinically apparent metastasis is between 20 and 30 years"

If cancer is really this ultimate chimearan opponent, why don't we put more
emphasis on detecting it during the _twenty years_ before it becomes
dangerous?

It would be difficult to detect changes at the cellular level at any location
in the human body. But it sounds like a problem that will scale with "Big
Data" a lot better than trying to fight evolution.

------
goronbjorn
Because it isn't nearly as important as Instagram, apparently:
[http://www.evernote.com/shard/s146/sh/eb8c59f9-44b5-48bc-a24...](http://www.evernote.com/shard/s146/sh/eb8c59f9-44b5-48bc-a246-30f7478c101c/7ff15abcd6a9d9d91c23c23f8408c908)

------
Apocryphon
It seems like there needs to be a combination of cultural/societal changes
favoring education in the life sciences, combined with funding. The launch of
Sputnik led to an upsurge of focus in math and science education during the
Cold War. To a much smaller degree, C.S.I. inspired a generation of forensic
scientists.

Maybe the startup response to this piece should be to figure out ways to spark
public interest in tackling this problems.

------
officialchicken
Which business model do you prefer - ongoing revenue or one-time payment?

There's more money to be made by treating the symptoms than there is providing
a cure. Anyone you know with a chronic disease will tell you that since their
diagnosis, the price of everything related to the condition has gone up
dramatically... cancer, ADD, diabetes, asthma, etc.

I wonder what ad-supported pharmacology business model would be like? Medicaid
meets Madison Ave.

~~~
Palomides
any corporation with a cure would have an immense advantage over any
competitors

~~~
Symmetry
Also, even if there were only one corporation with a total healthcare monopoly
then provided it could charge whatever it wanted it would still be able to
make more money by just curing the cancer since it's providing a more valuable
service by doing that.

------
krollew
I think that there is no widely known cure for cancer not because nobody know
one but because currently used cancer therapies are much more profitable. For
example there is something like Gerson's Therapy, I've never heard that
someone proved it wrong. Why it's not used widely? Because there is no money
to earn, there are just fresh vegetables so noone want to prove it right.

------
chmars
A major reason is probably nuclear pollution. Nuclear tests have been replaced
by radioactive waste and the results of many small and large incidents in
nuclear facilities. An accident like Fukushima pollutes the whole planet, not
just Japan and some parts of the Pacific. It would be much easier to fight
such major reasons for cancer instead of trying to cure cancer.

------
tsotha
Good God, this article is depressing. I used to think we'd have some therapies
to at least suppress new growth in my lifetime. If I'm understanding what he's
written they don't even have a game plan for an effective treatment.

~~~
crusso
That was my first thought too. I've always thought of cancer as being beatable
in ways that bacteria and viruses aren't since the latter get the benefit of
evolution. It makes a lot of sense that rapid evolution is exactly why cancer
has been so difficult to tackle.

The good news is that:

1\. Cancer survival rates have improved over the past and are continuing to
improve; so we're still moving forward. 2\. I have a lot of hope in the power
of technology to come to our rescue. a. Sequencing has to get to a point where
it's done in minutes or seconds on a chip. b. Physicians' computer aids need
to be Watson+. In order to be able to constantly categorize and target each
mutation with a drug or suggestion for other treatment. c. Ideally, we need to
get to the point where we can automate the synthesis of different types of
drugs so that the cancer attacking system can customize treatments at the
molecular level to dynamically attack cancers that are mutating.

------
mmphosis
because 99% of money raised to "fight" cancer is spent on finding a "cure"
whereas only 1% of money raised is spent on prevention. 0% is spent looking at
environmental factors:

\- nuclear waste alone: bomb testing in the 60's and 70's, uranium mining,
Chernobyl, bullets tipped with depleted uranium used in recent wars, Fukushima
Daiichi

\- systematic poisoning of the industrial food supply: genetically modified
food, petrochemicals, drugs that are put in food

\- systematic poisoning of the environment, water, air, and land.

------
alanh
Cynical answer: Because we keep inventing new carcinogens.

------
lucian1900
Well, we have cured many kinds of cancer. There are many more left, of course.

People looking for a general cure lose sight of the amazing accomplishments
already achieved.

------
throughnothing
Because "Cancer is Serious Business"
<https://www.youtube.com/watch?v=Be1ihuZNg84>

------
omerta
Not a surprise cancer hasn't been cured. Most diseases have not been cured,
yet. Even bacterial infections. People can still die from staph infections.

------
linker3000
Maybe we have...

[http://www.telegraph.co.uk/science/science-
news/9191848/Univ...](http://www.telegraph.co.uk/science/science-
news/9191848/Universal-cancer-vaccine-developed.html)

~~~
aakashamin
it's hype. Read the blog post!

------
gfodor
See also: "Facebook acquires Instagram [for $1B]"

------
Craiggybear
Because, like AI, molecular biology is complicated and _there are no quick
hacks_.

Some things are meant to take time and be right. First time.

Survival rates are spectacularly better than they were fifteen or twenty years
ago and they are getting better all the time.

Also there _is_ no one type of lung cancer, brain tumour or bladder or bowel
cancer either. There are many different types. Half the battle is identifying
(and successfully treating) the right sort.

I still think there will be cancer in fifty years time. But we won't have to
die from it. We may never eradicate it though, because it _is_ a tough,
complex bio-engineering problem, closely allied to programmed cell death and
immortality. That's another tough nut to crack for the same reasons,
inexorably intertwined as they are.

~~~
pessimist
Do you have a reference for survival rates? Note that there are many
confounding factors - lung cancer incidence has dropped a lot although lung
cancer itself remains intractable to average cancer survival rates may have
improved.

~~~
Craiggybear
Small cell, granuloma, take your pick. The data is available world-wide. The
fact is that lung cancer is one from which there is never a good prognosis
regardless of type. People can expect 4-5 years on average (although I know
people who have gone past ten and have a good quality of life).

It also is one where heredity and genetics plays an enormous role (as opposed
to purely environmental conditions).

Like I said, molecular biology is something we've only just _noticed_ far less
got a handle on.

Ars Longa Vita Brevis.

------
nextparadigms
I don't think we can cure cancer until nanotechnology tools can be used in
many hospitals. Send some nanorobots to eradicate all cancer cells in the
body, and that's it. But we're probably at least 20-30 years away from that.

------
millzlane
I have the answer. It's a simple one word answer. GREED.

But seriously It's the money that keeps us from curing cancer, or lack
thereof. Nothing else. As human beings we really need to decide what's more
important....Wealth or our survival and wellbeing. We're too smart as a
society to let things like lack of money keep us from curing disease and
exploring other planets.

~~~
aidenn0
It's not lack of money, it's lack of what money represents, which is goods,
services, and in general labor. If the US wanted to spend $100 trillion on
cancer cures it could, but the moment it printed all that money, the
purchasing power of it would decline to the point that they wouldn't actually
have enough money to cure cancer.

Consider a single cancer researcher. They need to eat. They need machines that
sequence genes that use techniques developed by other researchers, designed by
engineers, built by people in factories. All of those people need to eat. The
raw materials are mined out of the ground in work that is environmentally
damaging, hard work, and often dangerous work. It is not possible to snap your
fingers and have more work immediately happen.

There have been exceptions to the above, but it has been temporary in export
economies with exportable natural resources attainable at a below-market level
(e.g. OPEC, Soviet Union).

You can't just say "Is it really just money that keeps us from doing X?" since
money isn't the issue, it's that we don't have enough of the value that backs
the currency.

