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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...

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.




> 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.

No, they'll at best learn nothing, or more likely think they learn something and send the entire field off into the woods for a decade or two. Crack open "the Emporer of all Maladies" for a glimpse at just how difficult it is to judge effectiveness of treatments and preventions in even extremely controlled studies.

And your idea that somehow embracing quackery will lead to effective cancer treatments is just frankly insane.


just how difficult it is to judge effectiveness of treatments and preventions in even extremely controlled studies.

Translation: "just how difficult it is to be absolutely absolutely absolutely * 10^7 sure we're not selling quack medicine."

The treatment of Steveoma is effective if Steve gets better. If not, it isn't. The sample size is 1 by definition.

Obviously, if Steve gets better and he's taking 30 drugs, no one has any way to know which of the 30 worked, which were unnecessary, and which were actually counterproductive. But you still know more than you do when you started - you know that something worked. Lather, rinse, repeat.

And your idea that somehow embracing quackery will lead to effective cancer treatments is just frankly insane.

I love being refudiated in the morning!


I understand where your ideas come from, I wish they were true. But sadly they are misinformed on many levels, and the root of the problem is you are playing a statistical game where reality will win.

- There are not enough Billionaires to meet your needs, statistically you'll need quite a few to find any decent cures. Especially with 30 teams in play on each case; figuring out "what worked" is a bad numbers game in that case.

- Science shows there is unlikely to be one "magic bullet" for cancer, which makes it hard to cure individuals and then take that science into a wider populace; "something here worked, but does it work generally?"

- Cancer treatments are harsh and invasive - by design! 30-40 competing drugs is unsustainable, you would be, to put it mildly, royally fucked. So death could come simply by exhausting the body with treatment, as easily as anything else.

- You invoked Godwin's law, which is never a good sign.

I agree with your general premise; which is that it takes too long to iterate ideas into actual production. But the reason that scenario exists is not just "quack medicine" and other hopeful (but useless) remedies, it is for the case of "oh shit, I just killed a million people because we didn't investigate long term effects".

And that is where your theory really fails; because you are trading an unknown collateral now, for an unknown collateral in the future. I'm not arguing against either as a good or bad thing; but it does highlight the fatal flaw in the argument "you are killing X people right now by not releasing/iterating fast enough"


I have some questions about your points... How many people do you think one would need to find any decent cures/treatments? How many patients are current researchers making use of to accomplish the feat? If moldbug had said something along the lines of "you can increase the numbers by having billionaires fund people other than themselves, such as their parents or other people they care about, or just as donations, in ways that don't bankrupt them but still provide lots of experimental data", do you think the increased number could still not possibly be enough, would you still object?

If moldbug had started with 5 concurrent treatments instead of 30, would you object to that? (Though considering death is coming I personally would rather die of treatment exhaustion from X treatments than the actual cancer, knowing I tried many potential solutions. (This conditional on a cancer that actually threatens my life.))

Lastly, are the "unknown collaterals" equivalent unknowns? Shouldn't we try to estimate them and decide whether ramping up the release/iterate process is worth it? That people are dying because the research system sucks doesn't seem that controversial to me or very unknown in truth-value. How likely do you think it is that someone kills 1 million people with some remedy, and how likely do you think it is that the same 1 million people would have lived much longer without such a remedy being attempted on them?


I am going to echo Jach comments a bit. Millions of people are dying from cancer, and will die at the pace of current research. The argument is that if you turn up the pace, you will kill more people but in the longer term you may save a lot more. Instead of decades from idea to human trial you push into a few years.


Millions of people are dying from cancer, and will die at the pace of current research. The argument is that if you turn up the pace, you will kill more people but in the longer term you may save a lot more.

You can't predict these numbers though; which is my point. Neither is a very useful argument.

There are a lot of improvements that could take place; the moving of more drug research from the US to other countries, for example (that's probably a controversial opinion in itself).


Statistically you'll need quite a few

This is exactly the problem: statistics. In a problem where every case is unique, any use of statistics is an abuse of statistics.

The roots of Western medicine are arguably pre-scientific, and certainly pre-statistical. We knew and could do a lot of things before we knew what a p-value was.

If what "advancing knowledge" means to you is "accumulating p-values so I can publish papers," this kind of experiment can produce no information whatsoever.

If what "advancing knowledge" means to you is "we think we know what's going on and we think we can do it better next time," the answer is very different. Of course this is what most people, indeed most industries, mean by "learning." We don't have to know absolutely that we know - we don't have that luxury. Instead we need to get things done.

Modern scientific medicine is supposed - no, required (with the increasingly narrow exception of surgery) - to learn only in the first way. Guess what? It doesn't seem to be learning much. Or at least, much of any use. Maybe medicine isn't as much like physics as we'd thought.

it is it is for the case of "oh shit, I just killed a million people because we didn't investigate long term effects".

And you're lecturing me about Godwin's law?

For what it's worth, long-term effects of OTC non-cancer drugs aren't investigated for shit. I'm permanently achlorhydric from permanently solving my GERD with daily omeprazole. As recommended by actual doctors. What the hell is the effect of taking omeprazole for a decade? Who the hell knows?

And that is where your theory really fails; because you are trading an unknown collateral now, for an unknown collateral in the future.

Did you ever read Asimov's Foundation? Remember the bits set on Trantor? Your whole mindset is straight out of Trantor, I fear - and it's certainly not exclusive to you.


>Modern scientific medicine is supposed - no, required (with the increasingly narrow exception of surgery) - to learn only in the first way. Guess what? It doesn't seem to be learning much. Or at least, much of any use. Maybe medicine isn't as much like physics as we'd thought.

Hmmm: http://www.ined.fr/fichier/t_paragraphe/27734/paragraphe_img...

It seems we've doubled our life expectancy in the last 50 years. Medicine isn't working you say?

Look, I'm bitter as much as anyone else about the state of academics. I'm ex-academic-biology and have made no bones about it, here in this thread or elsewhere. But you are seriously characterizing the entire field.

Do you know why people are dieing from cancer? Because we've cured all the other diseases that killed them off at age 40.

Think about that for a minute.

Cancer is simply your body falling apart, going off the rails and destroying itself. It's doing that because, frankly, we were never intended to live 100 years. Thanks to modern medicine, we live well past the age that normal diseases killed our ancestors.

Our reward: battling cancer, instead of tuberculosis, pnemonia, cholera, gangrene or simply fever.


This point is so insightful and important, and I'm pointing it out in the hopes that more people will see it.


It seems we've doubled our life expectancy in the last 50 years. Medicine isn't working you say?

Mostly gains in infant mortality, plus antibiotics. We're coasting on the mid-20C golden age of medicine. Modern medicine is great - postmodern medicine sucks.

Replace "50" with 20 or even 30 and ask the same question.


For what it's worth, long-term effects of OTC non-cancer drugs aren't investigated for shit. I'm permanently achlorhydric from permanently solving my GERD with daily omeprazole. As recommended by actual doctors. What the hell is the effect of taking omeprazole for a decade? Who the hell knows?

Omeprazole has been about for nearly quarter of a century; and is fairly well understood - hell I can walk down to my local drug store and pick up a load from the shelves.

What you are describing, IMO, is either one of two things:

- a systemic failure in healthcare provision (not drug development)

- or a valid trade off between cure and side-effect

If what "advancing knowledge" means to you is "we think we know what's going on and we think we can do it better next time,"

The problem here is that you're going to kill a larger number of people in-trial due to mistakes or missteps. We know this because that is what early medicine did. Whether this is more than those who would die without aggressive research is something of a moot argument. Arguing the numbers is largely pointless because it's impossible to predict what will happen (that, after all, is the point).

Now; I see your argument that this is a valid tradeoff. Indeed, I think we should take more risks than we do. But not quite to the extent you are arguing.


Omeprazole has been about for nearly quarter of a century; and is fairly well understood - hell I can walk down to my local drug store and pick up a load from the shelves.

You say this like it follows.

I can too. I can read the label as well, which says to take it for no more than 28 days "without the advice of a doctor." Presumably this is the period for which it's been studied.

The idea of doing a double-blind study of the various systemic effects of a decade of induced achlorhydria is... absurd. How can you say it's understood? It's not understood, at all, either by my standards or yours.

So, without perfect information - I decide. I don't like the fact that all my ancestors for 100 million years had HCl in their guts, and I don't. I do like the fact that I'm not in the process of getting Barrett's esophagus and my abdomen doesn't hurt all the time.

Weighing risks and deciding without perfect information: fact of life. Trying to outlaw this process: like legislating that pi equals 3. Classic failure mode of the utopian 20th century.


Presumably this is the period for which it's been studied.

So, without perfect information - I decide.

The thing about the modern world is that you can make informed choices - information is only a Google away.

For example; my specific knowledge of that particular drug is not high. But this morning I found out:

- The drug is well researched as being tolerated in the short to medium term

- There is concern that long term use may increase the risk of intestinal or stomach cancers (based on mouse studies)

- So far the longest term test has been 6 years (somewhat longer than your 28 days theory).

In fact, 28 days is a standard recommended limit for drugs available over the counter. It is fairly hard to do damage to yourself, with those sorts of drugs, in that time - but after that you really need the advice of a doctor who understands all of the risks involved. Again, this detail is available online with a little searching.

There is a long list of other side effects, risks and theories that are studied - mostly based on 5 year studies from what I can tell - and the current view is that those risks are pretty low.

What you've proven, here, is that you've not made an informed choice, because you appear unaware of the actual long term concerns. You've not weighed risks; you've weighed one obvious risk that you understand (and I presume the doctor told you about). That is only the very tip of the iceberg.


- There is concern that long term use may increase the risk of intestinal or stomach cancers (based on mouse studies) - So far the longest term test has been 6 years (somewhat longer than your 28 days theory).

In fact, 28 days is a standard recommended limit for drugs available over the counter. It is fairly hard to do damage to yourself, with those sorts of drugs, in that time - but after that you really need the advice of a doctor who understands all of the risks involved.

I can't believe you just said "understands all the risks involved." On the basis of mouse studies and some completely uncontrolled, non-blind 6-year longitudinal study. Or meta-analysis. Or whatever.

Is this the best information we have or can get? Sure. Are the words understands all appropriate? No, they are not.

Aiming for this kind of certainty, and constantly, unconsciously boasting of it, is how postmodern medicine works itself into a box where it's completely unable to think. The information available in this case is shite. But the decision still needs to be made.


>The treatment of Steveoma is effective if Steve gets better. If not, it isn't. The sample size is 1 by definition.

Well, it's effective if Steve gets better than he would have if he hadn't taken it. That's a rather important distinction, and it's real hard to tell the difference with low sample sizes.


Spontaneous remission, while it happens, is not a significant confounding factor in pancreatic cancer.

See above for comments on statistics.


But in your sample size of 1, and later in sample sizes of all cancer suffering billionaires (lets also add in close family) a single confounding factor means that the resulting data is useless, and will only result in a wild goose chase for years to come.

Basically - any single chaotic factor outside the narrowly defined boundaries you have mentioned, will bork your entire system.

While this means that we've reached a similar state to where we are today, the current state is advantageous because it is systematic from the ground up.


Basically - any single chaotic factor outside the narrowly defined boundaries you have mentioned, will bork your entire system.

Sure. If you're stupid. Science isn't for the stupid. There is a common if implicit belief that systematic methods will allow the dull, or worse the dishonest, to advance the frontiers of knowledge. No - the rules of science need to be made for those both brilliant and honest. Everyone else has plenty of other games they can play.

Aristotle had a nice word for the intellectual quality it takes to learn from sample sizes of 1:

http://en.wikipedia.org/wiki/Phronesis


?

> There is a common if implicit belief that systematic methods will allow the dull, or worse the dishonest, to advance the frontiers of knowledge.

Ok, I'm taken aback by that - people actually think that people who are dull and dishonest become scientists? I mean I can understand that they become - frauds -. But scientists? Well maybe not in my country, but perhaps where you live.

Anyway thats just plain daft - the smartest become scientists.

>No - the rules of science need to be made for those both brilliant and honest. Everyone else has plenty of other games they can play.

Well, aren't the rules of science the scientific method? Which anyone can use?


Ok, I'm taken aback by that - people actually think that people who are dull and dishonest become scientists? I mean I can understand that they become - frauds -. But scientists? Well maybe not in my country, but perhaps where you live.

I'm afraid the problem is that my standards of both intelligence and honesty are much higher than yours.

Our society has far too many scientists churning out what Kuhn called "normal science." Look at all the scientists in the '70s and '80s who performed fantastic feats of normal science to sequence some gene or other. Science and society in 2012 are precisely as advanced as they'd be if all these researchers had been driving cabs.

Well, aren't the rules of science the scientific method? Which anyone can use?

Anyone can use a paintbrush, too. Not everyone can paint a Picasso.


> I'm afraid...

Oh I sincerely doubt that...


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.


My mother died of a malignant brain tumor at 55, 4 years ago.

Turns out, when your life expectancy is less than a year, you are willing to try a lot of things.

You know what's better than going to your granddaughter's wedding next month? Living long enough to see your granddaughters born.

My mother applied for every experimental drug treatment available. She got accepted into 1 out of 6. Her doctor told her it's standard practice for drug companies to deny access to experimental drugs if they believe the success rate is going to be low, because it makes their success rate look lower.

Think about that for a second.

The drug had already passed the safety trials, i.e. they knew it wouldn't kill her, but they weren't sure whether it would help her. The company thought there was a low, but not non-zero chance the treatment would work, and they denied it.

My mother knew she was going to die, she was grasping at straws for a cure. Trying new treatments isn't sacrifice.

The sacrifice is not doing and learning everything you can. The sacrifice is throwing away fully informed and willing test subjects, and having a bureaucracy that prevents people from trying to save their own lives.


I'm sorry to hear that your mother did not get access to a treatment that she wanted to receive. Clinical trials cherry pick the patients that they think will do the best. This is a dubious practice at best, but it is what they do, and they do it because as you point out, most new treatments have only an incremental benefit that is easily obscured.


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.


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?


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...

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


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.


Absent from your entire discourse, is any notion of a good death. I've looked after people who wanted to try everything, fly anywhere, even when they weren't strong enough to sit up in bed. They didn't die well.

It has never been shown that treating cancer patients up until the time of death makes any difference to either quality of life or survival (http://www.biomedcentral.com/1472-684X/10/14). Sometimes there is a tyranny about the biology of cancer that is difficult to overcome even with agents that are known to be effective, not even when you have run out of all drugs completely.

You might scoff at the notion of a good death. But then there is this trial (http://www.nejm.org/doi/full/10.1056/NEJMoa1000678). This was a trial which compared early palliative care with late palliative care involvement for patients with metastatic lung cancer. They were otherwise treated with standard therapy/clinical trials/whatever was available. Astonishingly, those patients that received early palliative care had less treatment overall and lived nearly 3 months longer - by getting less treatment, and focusing on quality of life. If there was a new drug that helped people with lung cancer live 3 months longer, it would be revolutionary.

On the basis of this evidence and my personal experience, I believe there is potential harm in taking the attitude of wanting to try everything by default. This attitude may be right for some people, but for others, it may shorten their lives for no benefit and leave them and their families unprepared for the inevitable end.

There is no escape from the notion that the latest drug might just turn everything around. It is certainly true that when a drug like this comes along, there will be some people who miss out and die because they or their doctors didn't try hard enough. But how much potential harm can you justify because of this tiny, tiny risk?


[There's a TL/DR at the bottom]

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. You're absolutely right that this is the mentality that future treatments need to take. In terms of treatment response, a liver tumour could have far more in common with a brain tumour than another liver tumour - the anatomical pigeonholing of cancers is a throwback to pre-molecular diagnostic times (so about 5-10 years ago and before) and is something that will hopefully change over time.

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. If this time frame were possible this would be ideal, however, unfortunately each of these steps (if they are possible) takes significantly longer than an evening, and typically far longer than a patient has.

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. This is a risky game. How do I (the scientist) know which drugs were effective? How do I know how they'll react with one another? If my focus is Steve, then do I really want to risk killing him through an unexpected cross reaction of my 30-40 untested drugs?

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. How many billionairs? There are (apparently) 1210 billionairs in the world. So say they all get cancer and get this team of doctors - if any of the patients survive then some aspect of the treatment worked. If they don't some aspect failed. It would be impossible to determine which is which. Considering the heterogeneity in terms of cancer genetics, 1210 would tell you very little at the genetic level.

You'll note that a lot of cancer patients die anyway. But a lot fewer than used to.

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. This is not the problem with drug discovery (or correct).

[TL/DR] There are aspects of this which ring true (reproducibility is an issue, although how you measure it is also a source of contention, and mouse models have their downside, certainly), however, there are also gross assumptions and misunderstandings which would make this course of action as ineffective as it would be expensive. There is an absolutely imperative need to begin to asses and describe cancers as more related to a patient than a disease title, you are quite right. But to forgo basic research in favour of arbitrary treatment-come-experiments would be to dismiss the last 100 years of biological research which have provide us in a position where you can make your argument. A combined focus of translational and basic research is essential, with a frequent and effective dialogue between the two.

Ultimately, your argument assumes the rate of discovery will be constant. You need to consider the research in the broader picture. Cancer is a genetic disease (in terms of pathological origin, not necessarily in hereditary terms). It cost the (publicly funded) human genome project $3bn to sequence a human genome in about 12 years. Now it costs $5000 in a week or so, and both the cost and the time is coming down. As I said before, it is an exciting time to be a cancer biologist.

-- I can't reply again, but, um, are you trolling?


I can't reply again, but, um, are you trolling?

I didn't see this message the first time. Truly remarkable comment. Am I trolling?

I'll answer with a text from 1863, by the English historian James Anthony Froude:

In the ordinary branches of human knowledge or enquiry the judicious questioning of received opinions has been regarded as the sign of scientific vitality, the principle of scientific advancement, the very source and root of healthy progress and growth. If medicine had been regulated three hundred years ago by Act of Parliament; if there had been Thirty-nine Articles of Physic, and every licensed practitioner had been compelled, under pains and penalties, to compound his drugs by the prescriptions of Henry the Eighth's physician, Doctor Butts, it is easy to conjecture in what state of health the people of this country would at present be found.

Constitutions have changed with habits of life, and the treatment of disorders has changed to meet the new conditions. New diseases have shown themselves of which Doctor Butts had no cognizance; new continents have given us plants with medicinal virtues previously unknown; new sciences, and even the mere increase of recorded experience, have added a thousand remedies to those known to the age of the Tudors.

If the College of Physicians had been organised into a board of orthodoxy, and every novelty of treatment had been regarded as a crime against society, which a law had been established to punish, the hundreds who die annually from preventible causes would have been thousands and tens of thousands.

I suppose it's trolling to remark that Doctor Butts has made quite a comeback. Source: http://books.google.com/books?id=Xc0YHClRwA4C.


You're absolutely right that this is the mentality that future treatments need to take.

Yeah, and I'm sure our regulatory infrastructure will catch up sometime in the Obama administration. That is, the Malia Obama administration...

If this time frame were possible this would be ideal, however, unfortunately each of these steps (if they are possible) takes significantly longer than an evening, and typically far longer than a patient has.

Then speed them up! You might have heard the story of Steve and Gorilla Glass:

http://en.wikipedia.org/wiki/Gorilla_Glass

You're not going to tell me the actual chemical reactions are slow. It's all human labor. The speed of any organization is limited by the schedule on which results are demanded - compare the Manhattan Project to the new Bay Bridge.

This is a risky game. How do I (the scientist) know which drugs were effective? How do I know how they'll react with one another? If my focus is Steve, then do I really want to risk killing him through an unexpected cross reaction of my 30-40 untested drugs?

Yes, because Steve knows he's at risk of dying anyway. Being an intelligent person, Steve compares the risk of dying from neglect, versus dying from treatment, as apples to apples. Do you?

There are (apparently) 1210 billionairs in the world. So say they all get cancer and get this team of doctors - if any of the patients survive then some aspect of the treatment worked. If they don't some aspect failed. It would be impossible to determine which is which.

It would be impossible to determine which is which by the present statistical standards. Ie, it would be impossible to absolutely absolutely 10^7 know which was which. It might be possible for an intelligent person to make a good guess, however.

This is how technique advances in any technical field that can't be reduced to pure mathematics. If you're limited to advancing on the basis of perfect truth that absolutely * 10^7 knows it's right (even if when tested in practice, it's 90% irreproducible), you can barely advance at all. Guess what - we're barely advancing at all.

A combined focus of translational and basic research is essential, with a frequent and effective dialogue between the two.

The best way to have a frequent and effective dialogue is to make basic researchers part of the teams treating patients. The distinction is imaginary, anyway.

This was I believe the case for Steve, but not even for Steve could they do personalized drug development as described. They couldn't even try drug candidates which other developers and/or researchers had abandoned along the way - an enormous library of molecules, if properly collated.

Ultimately, your argument assumes the rate of discovery will be constant. You need to consider the research in the broader picture. Cancer is a genetic disease (in terms of pathological origin, not necessarily in hereditary terms). It cost the (publicly funded) human genome project $3bn to sequence a human genome in about 12 years. Now it costs $5000 in a week or so, and both the cost and the time is coming down.

It's a separate discussion, but you're actually making the argument against investing in basic cancer biology. Rather, all the investment should be in sequencers, etc.

Reason: consider the studies you did with the tools of 10 years ago. What was difficult then is trivial now. So in what way did it contribute to what you know now? In no way, which makes it useless - if you hadn't done the work then, expensively, you could do it now, trivially. Now, consider the studies you'll do with the tools of 10 years from now...

Of course, the practical effect of funding cancer biology is to fund tools development. But it's a somewhat indirect way to accomplish the objective...


>You're not going to tell me the actual chemical reactions are slow. It's all human labor.

I'm going to tell you that you are, in fact, wrong. Chemical reactions (pharmacodynamics) may be fast, but pharmacokinetics may very well be slow. There is a reason you have to take antibiotics for at least two weeks, or wait three months to see an effect from SSRIs.

These things literally take time. Not all processes are instant in your body, many take time for their physiological effects to be materialized.

Biology is biology and not everything is instant, no matter how much you wish it was.

>Then speed them up! You might have heard the story of Steve and Gorilla Glass:

This is such a naive comment I'm not really even sure how to address it. First, you can't just "hack" a molecule in a night.

Identifying the protein targets could be a lifetime's work. Identifying drug interactors is another big project, verifying efficacy takes time, synthesis takes time, verifying purity, determining best method of delivery to the patient, half life, dosage, interactions with other drugs, on and on and on. It all takes time.

Second, even supposing we can make a specific molecule overnight, the chance that molecule is going to kill your patient is really damn high. The human body does not get along well with most chemical compounds. There is a reason we have extended, long clinical safety trials. While you can make an argument they are too long, "overnight" is far, far too fast.

You'll never know if you cured your patient's cancer when he drops dead tomorrow from your sulpho-cholorinated-methyl-mercury superdrug cocktail that you synthesized last night.


Identifying the protein targets could be a lifetime's work. Identifying drug interactors is another big project, verifying efficacy takes time, synthesis takes time, verifying purity, determining best method of delivery to the patient, half life, dosage, interactions with other drugs, on and on and on. It all takes time.

Look, I'm not an idiot. I know it takes 10-20 years to develop a drug. But I also know that many of the drugs we use now were developed before any of these processes existed. Aspirin anyone? Penicillin?

All of the processes and techniques used by the present-day pharmaceutical industry are predicated on the cultural assumption that, as I said earlier, it's better to let a thousand patients die of neglect than kill one with a drug. In fact, three orders of magnitude may be understanding the asymmetry - it might as well be six.

Once you learn how to do things incredibly slowly, incredibly expensively and incredibly carefully, you're going to be completely ignorant of any way in which they might be done "fast, cheap and out of control."

Very much a parallel situation is the nuclear industry. Does it really take 20 years to design and build a nuclear reactor? Done the modern American way it does. And indeed, there's a much better argument for nuclear overregulation than cancer drug overregulation - still not a good one IMHO.

There's plenty of experience from military programs, even from the other side of the Iron Curtain, that tells us it's not that difficult, slow or expensive to build a nuclear reactor. But if you ask any nuclear professional, you'll be asking someone who knows in great detail how to build reactors the ultra-paranoid way. As far as he's concerned, that's the only way to do it.

Nobody in the pharmaceutical industry knows how to execute effectively with a short OODA loop. The knowledge and experience would have to be created, certainly at the cost of errors and lives. That's a far cry from saying that it cannot possibly exist.

Think about the way weapons are tested and deployed, not in the play wars we fight now but in a real war like WWII. Many, many soldiers in WWII died from unanticipated weapons failure. But if weapons hadn't been developed with the tightest possible OODA loop, we'd have been fighting Tiger tanks with cavalry lances.

We're not fighting a "war on cancer." The military psychology is entirely absent. We're playing a game. As an earlier poster said, "it's an exciting time to be a cancer biologist." Is it an exciting time to be a cancer patient?


Well first, I don't think you're an idiot. I haven't downvoted a single one of your comments because I think they are all constructive and thought-provoking...even if I don't agree with many of your points. =)

Regarding Aspirin, Penicillin, et al, many of those drugs are the low hanging fruit in pharmacology. We've already plundered many of the easy molecules. I would contest that many of the present-day pharmaceutical assumptions are predicated on the fact that the easy molecules have already been found.

The reason many drugs fail is not because clinical trials are too long - its because the drugs themselves prove ineffective, unsafe or both. Is a 2% increase in survival rate worth a 20% increase in mortality due to complications and side effects?

We are past the days that you can find compounds that mold poops out, and use it to cure 90% of humanity's ailments.

I certainly agree that clinical trial regulations are too long, with too much bureaucracy. They could stand to be shortened considerably. BUT, they also exist for a reason - safety is important.

Also consider the safety of the patient. Cancer patients are usually willing to try anything to avoid dieing of cancer. There needs to be some protection such that these people are not unduly taken advantage of.

There is a fine moral line between allowing people to take risky drugs to cure their disease and allowing companies to treat cancer patients as expendable hamsters.

*Side note: I am no fan of big pharma either. They are effectively marketing firms that sell pills, not research companies (anymore). But that is not really what we are discussing at present =)


It's because the drugs themselves prove ineffective, unsafe or both.

Statements like this prove the systemic abuse of statistics that is pharma regulation. You've - quite unconsciously, no doubt - reversed the definition of proof, asserting that failure to prove a positive is equivalent to proving a negative.

Of course you don't believe this. But your institutional jargon automatically generates the lie. Orwell had a point.

Today's viable drug is a survivor in a winnowing process in which any of a thousand screwups - often mere failures of trial design - can kill it. Moreover, while some of these are corporate errors (not the drug's fault), many of the design failures are institutional and uncorrectable.

For instance, testing cancer drugs of the "magic bullet" type against late-stage tumors is utterly ridiculous, as these genetic Cthulhus are the last place anything targeted is likely to work on. But this is the only place our testing paradigm is viable. The drunk looks under the lamppost for his keys, again and again.

Advanced genotyping might reveal that a certain tumor has five pathways for evading apoptosis. Five different molecules are needed to shut them all down. In an individual trial, each molecule fails. It thus - to use your language - "proves ineffective."

We are past the days that you can find compounds that mold poops out, and use it to cure 90% of humanity's ailments.

It's a commonplace assertion that most of these older compounds (certainly aspirin and penicillin) would fail an early toxicity screen and never get close to a mouse, let alone a patient.

I have no idea whether this is true. But if it is, Western medicine is objectively in the same position as NASA: it can no longer do the things it did 40 years ago. Welcome to Trantor.


Yes you are a heretic and yes you are exactly right and yes you will be mocked/derided for it.




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