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.
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.
A few years ago I did an analysis on common chromosomal deletions in ovarian cancers. I was hoping to find some sort of "required" genetic or metabolic structure retained by the various cell lines. Nada. It was just a big unrelated mess and deemed not interesting enough to write up by my advisor. I wish there was a Journal of Dishearteningly Negative Results.
It makes sense to me. I once read a lung cell has to evade seven different anti-cancer mechanisms to become a malignant stem. If there are ten different ways to get around each defense, that would mean ten million different possible configurations of lung cancer, with all the therapeutic headaches that implies.
Edit: And that's just for one cell type out of the myriad that compose a functioning lung.
"Cancer isn't like a virus or pathogen that has evolved to avoid it our immune system..." until it start reproducing at a quick rate -then, as the article says "Tumor cells undergo evolution as they grow, so that the cells in them are genetically heterogeneous.".
But another thing to think about is that science based medicine has so far been more or less powerless against degenerative diseases - in general. Our treatments for cancer, heart disease, arthritis and so-forth as basically ad-hoc as contrasted with our treatment of externally-caused disease.
And this isn't surprising given that a degenerative disease is essentially a breakdown in engineering of the body and we essentially don't have a clue how to re-engineer or repair those processes (with many fine exceptions but they are exceptions).
The genetic diversity that the author talks about in cancer is basically present fully functional human beings. The way that different people function is far more different than even the way two different cars work. When human any part of a human being breaks down, we can't in general produce a replacement. Sure, there are advances in understanding the processes involved but these are, again, ad-hoc so far.
Evolution does occur in cancer cells in the sense of increased genetic variability which may lead to more aggressive/resistant cancer in a patient. However we won't see things like drug resistant staph infection because the genetics of the tumor don't spread beyond the individual.
I also agree that our understanding of degenerative diseases is poor but I think that modern technology and methods will change this. Hopefully to the point were we can prompt the body to move the body from a diseased to a healthy state but that may be a ways out.
However the genetic diversity in cancerous cells is not present in functioning human beings. Based on the analysis of genetic sequence data from tumor and blood samples from the same individuals it is clear that a large amount of mutation and structural variation occurs in cancer cells.
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]
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.
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.
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).
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?
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.
Hundreds of millions of dollars and years of clinical trials are needed to prove if DCA is effective or not. You can't just say "trust me, they looked into DCA and found it wanting". Looked at it how? Have they done years of clinical trials? did they spend millions in R&D on this?
There have been small clinical trials of DCA conducted already. That data is out. They were not compelling enough to warrant the type of investment you are talking about (multi-year clinical trials).
That's not to say it may not be found effective for some types of cancers in the future. But what it does tell us is that the lack of interest in spending more money on r&d is not some conspiracy by pharma because they can't make money on it, rather, it's because the data just hasn't been that impressive so far.
To be fair, it is only one of many compounds that are effective against specific traits of cancerous tumors. In this case, it is effective against tumors which are poorly vascularized.
In most cases, one of the predominant features of tumor progression is the increase in vascularizing growth factors from cancer cells. Tumors which fail to start pumping out growth factors that encourage blood vessel growth often kill off the entire tumor due to lack of oxygen.
Also, the apoptosis cascade can be hijacked in many locations. Even if you get the mitochondria to start releasing Cytochrome C (the main component that triggers the cascade), cancer cells can turn this pathway off anywhere downstream of CytC, such as turning off production of one of the various caspases.
So, again, it comes down to cancer biology being incredibly complicated.
DCA is an unfortunate example of the pattern where people look for a radical cure covered up by conspiracy when infact it is little more than a mildly interesting drug with little evidence supporting its use.
So far as the conspiracy theory goes, to quote the same Wikipedia article:
The use of this compound as an anti-cancer agent has been patented.
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.
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.
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...
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.
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.
> If something is "ten years away", it means we simply don't know how to do it
In terms of medicine, human trials generally take ten years. If something is ten years away, I would take it to mean there is a promising solution now. It just might not look nearly as promising in ten years, after it has been rigorously tested on people.
I think you are unduly pessimistic. Medical progress is slow compared to IT, but 100 years ago we didn't even have antibiotics. Now we have defeated smallpox and polio ("few of the doozies"?!?), and we make progress in other areas.
We can cure (some of the most common forms of) blindness[1]
We can't cure AIDS, but anti-retroviral drugs can stop HIV infection from becoming AIDS[2].
We can't regrown limbs, but we can regrow ears[3].
Even cancer is slowly being fought back[4]. 20 years ago no one thought the HPV vaccine was possible, and yet now it will protect the ~11,000 US women per year who would previously been diagnosed with cervical cancer.
I totally agree, but it doesn't explain why there are so many treatments not available in the U.S., but available elsewhere. Islet cell graphs, for example.
Personally, I'd encourage EVERYONE with a chronic disease to become a quant, so that they may live long and healthy lives (after leaving finance).
- 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.
>- 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.
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.
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.
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.
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.
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.
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.
But with better compensation you would have brilliant minds who are only interested in a paycheck looking into the data as well and they would still produce results. Frankly, I'd rather these greedy minds look for cancer cures than into creating new exotic financial instruments.
... Because (the US at least) spends way too much money on war instead of curing disease, becoming energy independent, and educating our next generation.
Nobody feels the need for a cure for cancer until they actually get cancer, and until then its always US and THEM. People take photos and share them all the time. So Facebook sells. So Instagram sells for a $1 billion.
Unfortunately we don't act until we are forced to.
1) is simply not true everywhere. I'm sure it varies depending on a country, but I know PhDs in a number of fields and all of them are doing at least "ok" financially.
I'd like to see any kind of proof of 3)... it may be actually the opposite, because it shows that if market has enough money for a dotcom bubble 2.0, some of the transaction value is likely to fuel research to some extent (via taxes, etc.). Good economy is good for many people. (simplified, but true to some extent)
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%).
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.
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.
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.
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.
Changing of allele frequencies can occur by creation of new alleles (ie. mutations), but it doesn't have to. The definition encompasses both possibilities.
I'm voting this one up. I think that curing cancer is like eliminating all errors in a program. Cancer cells are simply cells committing mutiny and forming new organisms behind the defence lines. Like other inner enemies like spies this will remain one of the trickiest risk factors to eliminate, since they are simply parts of your organisation turned against you. If you get better, so do they.
Given the unbounded complexity of 'some part of our organism gone haywire' our best bet against cancer is probably an early detection and general purpose defence system like the immune system that we already have. So finding a one true cure for cancer is probably a utopia. The more complex the immune system, the more complex the threats that do outsmart it will become.
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...].
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.
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:
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:
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 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).
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.
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.
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.
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:
> 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.
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:
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?
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 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.
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:
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.
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...
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.
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?
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.
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.
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.
A minority of NFL revenues come from ticket sales & merchandising combined. Much of it comes from advertising. If you're an effective channel for mass attention, it stands to reason that you're going to be poised to capture huge amounts of money, simply because there's huge amounts of commerce happening.
The NFL's revenue is not really a reflection on our priorities. A better comparison would be to other discretionary expenditures in the federal government.
> The NFL's revenue is not really a reflection on our priorities.
Isn't it reasonable to assume that, if costumers had different priorities and seek for science research news more often. Then advertisers would, maybe, consider investing in science research instead of football? If we could, somehow, teach and get people interested in science. Then having your brand name associated with the cure of cancer could be more valuable than having your brand associated with football.
It just seems to me that it's a matter of whose priorities are we talking about. You're not wrong, but I have the impression you and noonespecial are talking about different things.
People aren't buying football advertising to associate their brand with football. They're buying advertising because during football games, millions of people are paying attention to a specific TV or radio station.
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.
> 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.
For what it's worth, I'm a scientist and I agree with you wholeheartedly. Many of my colleagues do as well. (Full-disclosure: I'm still an 'undergrad', but most of my courses are independent research.)
I don't cut out fun entirely, but I do tend to overwork. I'll be dead soon and have no recollection of 'fun', so I tend to prioritize/maximize my traversal time spent doing academic 'activities' (which are rewarding in their own right).
I still require a basal level of fun to stay sane, though; it would be interesting to quantify it...
Agree, but as tptacek pointed out, there's a lot of commerce happening in football. If majority will shift their concerns to health problems, then the commerce will be happening there. Not sure if it would be necessarily a good thing, and it likely would require strict regulation.
Although I understand your point, there is a limit to the rate in which you can even spend cancer research money, even if you wanted to dramatically increase it. For one thing, you are limited to funding the research that you think will lead to a cure. It may turn out that the level of funding for direct cancer research is fine but what is needed is increased funding for nano-robotics or strong AI, or supercomputers that can simulate tumor growth and evolution. The linked article was very sobering indeed; finding a cure for cancer almost seems like trying to find a grand unified theory for physics. It may turn out that you basically have to figure out how to cure all diseases in order to cure cancer.
I for one find cancer research much more fascinating, there are always new surprises and twists to learn and discover. With a football game, we already know the rules, the outcomes are not all that diverse, and people have been playing the same kind of game for ages, I get bored really fast.
Maybe there are some ways to make it more entertaining? http://eterna.cmu.edu/ , google image labelling and other "gamified work" projects come to mind.
Or a slightly more weird way to put it... we make a big show of music auditions where millions of people get super-excited and spend money to vote on a person they will most likely never see again in their lives. How do we get people that excited about science?
What I really wanted to say was that its quite likely that society spends more (much more) on sports entertainment than medical research. Perhaps not wrong. Interesting though.
What's the point in singling out sports entertainment?
Apple cleared $100bb predominately selling consumer electronics, should everyone who bought an iPad feel bad for not donating that $600 to cancer research?
Facebook just threw a billion around on a photo sharing company.
Microsoft just threw a billion so it could acquire some more patent ammunition.
Everyday billions and billions of dollars are thrown around to buy all sorts of things, who gets to decide what spending is "right" and what's "wrong?"
Heh.. Perhaps you might use an apple computer to help cure cancer and you probably wouldn't use a football?
>who gets to decide what spending is "right" and what's "wrong?"
None. Noone. Perhaps not wrong. Interesting though.
Sorry guys, guess I kind of ran this one right off the rails. We underspend on medical research proportionally. That was all. I just tried to pick something a little more interesting than the TSA to joust at this time.
Picking a few billion that sports makes rather than the lots more billion that tech makes feels a little like pandering to the crowd, though (we're geeks, stereotypically don't like sports and "jocks"). A more edgy question, given the audience, would be to ask why our priorities are such that we pump much more money into web startups than cancer research.
Perhaps some scientist gets a new idea while relaxing to a game of football ... you can't really predict what would happen to our society if you start playing around with priorities. Historically such decisions had awful consequences.
Also sorting out the priorities of our society means getting rid of capitalism, and finding
a new economic system that works better is (arguably) a harder problem than currying cancer.
When you factor advertising out of the NFL, NBA, and MLB, I'm not convinced that all three together outstrip medical research. Pfizer alone has an R&D budget higher than the NCI.
I really don't think this is a valid comparison you're making.
I agree that it's unlikely that medical research is less well funded than sports. I do think it's plausible that "critical" medical research (excluding ailments like small-penis and spring allergies) is less well funded than sports, for some reasonable definition of "critical", but I'd be unwilling to put any money one way or the other without doing a bit more research.
I will say, however, that pharmaceutical companies put a tremendous amount of money into researching and marketing treatments for common minor ailments.
When you say "better funded than sports", you're implicating advertising. But advertising revenue is in part of function of the broader economy. F-500s don't buy Super Bowl ads because they love football.
Well, let's not get excited here. I don't think anybody is saying that they think there's some capitalist in a top hat allocating funds, saying "We will put $4B into cancer research to keep the eggheads quiet, and $9B into football to distract and pacify the proles." At least, I hope nobody thinks that.
But the point is that when we, as a society, allocate resources this way, it is an indication of pathological economic behavior, and we need to find solutions for that.
Don't forget the other costs of "moneyball" like giant stadiums every 10 years or so in every major city reorganizing the entire downtown as they are built.
Mostly I agree with your above point about discretionary government spending though, but it would have been pretty low hanging fruit to just say (once again) that the money spent saving us from terrorists would save a lot more of us from cancer.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
But the discipline isn't even 100 years old yet, and really only in the last couple of decades have we been able to have technology to really take advantage of isolation. We have learned so much about modern medicine, but have so much more to go.
Cancer survival rates are a mixed bag with many barely moving at all. The statistics below are based on that for Victoria, Australia (population of about 5.5m).
5 year survival rates for the following cancers has barely changed at all since 1985: Pancreatic, Larynx, Lung, Mesothelioma, Ovarian, Cervix, Central Nervous System.
Although the following cancers have seen much better improvement:
Pharynx, Colorectal, Stomach, Oesophagus, Gallbladder, Breast, Prostate, Kidney, Thyroid, HL, NHL, MM, ALL (basically all the blood cancers).
Overall the 5 year survival rates for cancers have improved from 47% to 64% now. Definitely better, but unfortunately not "spectacularly better".
Of course, these are survival rates, so do not reflect improvements in public health that prevent people from getting cancer (e.g. survival rates for lung cancer have have actually decreased, but less people are acquiring it due to reductions in smoking meaning deaths have reduced by about 50%).
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.
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.
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.
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.
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.
It's not lack of money at all. How many researchers, worldwide, do you think have the expertise necessary to make a nontrivial contribution?
The problem is we simply don't have the technology to develop a cure for cancer, and we don't even know the precursor technologies we need to develop a cure for cancer.
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.