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Andy Grove has had prostate cancer, and now suffers from Parkinson’s, so it’s no wonder that he’s taken aback at how poorly we understand each of those diseases – not to mention all the rest of them. But his experience in the technology world has warped his worldview. We are not suffering from a lack of urgency over here – talk to anyone who’s working for a small company shoveling its cash into the furnace quarter by quarter, or for a large one watching its most lucrative patents inexorably melt away. And we don’t suffer from a lack of hard-charging modern management techniques, that’s for sure.
What we suffer from is working on some of the hardest scientific problems in the history of the species.
Once you build a system that builds treatments for specific problems, you treat the problem and repeat as they come up.
Not dying of the first cancer is better than dying of the first.
Just because there are N cancers in the series doesn't mean the problem is impossible, it just means we haven't ever gotten past the first levels to figure out how it works.
The secret to winning pacman isn't 256 separate strategies, it's a small set of strategies that fit together once you know how the game changes level to level.
The author is just fixated on the fact they finished the first level AND THE WAS ANOTHER!
> Cancer relates to our fundamental constitution as multicellular organisms, our limited lifespan, the epidemiology of the aging population, socioeconomics and the future of society.
This is the most important part. Life is cancerous. When people claim to cure cancer it's sort of an oxymoron. There are indeed no such things as cancer genes but more like a breakdown in the cooperative biochemical networks that make multi-cellular life possible. It's actually a great wonder how all those cells in your body manage to cooperate at all without stepping on each others' toes all the time.
In a way the delicate balance is a constant fight against entropy and entropy always wins. Enough breakdowns and misunderstandings in the biochemical networks and the multi-cellular ecology and you have cancer.
> When people claim to cure cancer it's sort of an oxymoron. There are indeed no such things as cancer genes but more like a breakdown in the cooperative biochemical networks that make multi-cellular life possible.
This description fits scurvy fairly precisely. But no one would say it's nonsense to talk about "curing" scurvy. Give someone some vitamin C, and their scurvy will be cured.
Would you also say it's an oxymoron to talk about "fixing" software bugs because the terminology assumed they were designed in?
If you look at how cells work on the micro-scale it looks a lot like cancer. They constantly divide and try to proliferate by allocating and using resources. The only thing keeping them in check is basically the "cellular honor code". You can certainly try to make it less likely any given set of cells breaks the honor code but you can't "cure" cancer. It's an inherent property of multi-cellular life. Not unlike bee and ant colonies. There is always one queen (or several) but sometimes there will be a rogue queen born that bifurcates the colony. Bees and ants go to great lengths to avoid these situations but the way colonies are set up and structured rogue queens are an unavoidable part of the colony given a long enough timeline.
I characterize scurvy as a sub-optimal stable operating state where optimality can be restored. Cancer does not have similar characterization. It's more like an unstable runaway loop.
But I'm neither a biologist nor a doctor. My understanding is basically a bunch of analogies between game theory and general systems in the context of biology and maybe that's not the proper set of analogies for the problem at hand. In that context cancer is the breakdown of feedback loops that keep the system stable.
> I characterize scurvy as a sub-optimal stable operating state where optimality can be restored.
This makes no sense. It's not a stable operating state. Vitamin C is necessary to hold your cells together. Scurvy is the failure path of not having vitamin C; it is a transition from "healthy" to "dead".
> cancer is the breakdown of feedback loops that keep the system stable
OK, but this is exactly what scurvy is. They're just different feedback loops. Infection by foreign bodies is also "the breakdown of feedback loops that keep the system stable". Your objection applies to everything, which makes it completely meaningless when you apply it to cancer specifically.
This whole conversation reminds me of http://lesswrong.com/lw/iv/the_futility_of_emergence/. Claims like "breakdown of feedback loops that keep the system stable" are basically just a long way of saying, "for reasons I don't understand." All things happen for reasons, and if it's on the bleeding edge of human understanding, or beyond current science, it'll likely be for reasons you don't understand. That does not mean that no entity will ever be able to understand.
It's a little frustrating honestly. Don't people see that most things seem impossible until they aren't? Just two years ago a lot of people were quite confident that computers would never surpass humans at Go. https://www.reddit.com/r/baduk/comments/2wgukb/why_do_people... This is one of dozens of such links you could find from that period. Much moreso ten years ago. I get that cancer is a horse of a different color, but come on. If you are confident that ANYTHING will be impossible in 200 years, besides things which are physically so . . . well, I just cannot agree.
Stable/unstable/negative/positive feedback loops are technical terms in control theory (https://en.wikipedia.org/wiki/Negative_feedback). I'm using those terms for specific reasons. I don't quite see what you're objecting too. Studying biology in the context of systems and control theory is a pretty well-trodden path (https://simple.wikipedia.org/wiki/Krebs_cycle). Much of modern pharmaceutical research is actually about uncovering the chemical governing loops (another technical term) and affecting them to achieve positive outcomes.
Cell division is an unstable positive loop that requires dampening with negative feedback loops at higher organization levels. When those negative feedback loops break down you get an unstable positive loop in the form of cancer.
So you see how having cell division in a multi-cellular context can not be "cured" of cancer? You'd need to stop cell division and somehow figure out a way around entropy. Cells divide to renew/reset and shed accumulated environmental damage. So no matter what you do as long as you have a system organized around unstable processes like this you will always have a control problem when the negative control mechanisms stop working.
As I've already pointed out to you, every biological system is a feedback loop in the sense you describe. Feedback loops are how you defecate, how you blink, how you move, and how you choose how much of what to consume. Feedback loops regulate the activity of your immune system and seal the holes in your skin when it's punctured. This doesn't distinguish cancer from anything else.
The universe is logical. Each cell in the human body is at its core just a very complex state machine.
What we call cancer is just a particular state for a cell, and its descendents.
Find a way to change the cell state, we end cancer. And we know we can change a cell state-we can transform skin cells into stem cells, so what would make it impossible to turn cancerous cells into non-cancerous cells?
We just haven't found out the proper way to do so. It takes data, and simulation, and lots of time. At some point we'll figure it out.
I think the only misguided attempts are chemotherapy-based - damaging cells indiscriminately, just because cancer cells multiply faster and thus accumulate dna damage faster and thus die faster than normal cells. This means that unless you kill all the cancerous cells your cancer will come back. The problem is chemotherapy drugs will also be damaging your body in other ways, depressing your immune system, and thus making it easier for any remaining cancerous cell to start it all over again.
I believe it's much easier to simply figure out the right cocktail that would change cancerous cells into normal cells again, and then find the delivery mechanism for that.
I can see a future where we can transform cancerous cells into cancer-killing cells (let's say T/B Cells) that would just cascade into the complete eradication of cancerous cells within an organism.
This guy's argument boils down to lack of imagination.
He does spell out why he doesn't subscribe to that approach:
"Cancer cells are not simply a disorder or breakdown in a mechanism, but an organism going on a full-tilt offensive, using multiple, often shifting strategies to produce and use molecular fuel, win resources, and evade the immune system. If so, then the rules of the game may change—these insights suggest that the war on cancer may be endless."
I don't have any expertise here, so I'm not saying he's right or wrong. But it doesn't seem to be a lack of imagination.
The author does not lack imagination. You may, however, lack knowledge of biology. What you're boiling down to a "cell state" represents dysregulation of the most complex object in the known universe. A single human cell is vastly more complicated than anything made by mankind.
I agree with your point, but am always a bit put off by these "most complex ... in the known universe." It's something that people say that doesn't really hold up to cursory scrutiny.
E.g. we think of stars as big balls of fusing matter. But that's an idealisation. Is a star really less complex than a human body? It all depends on which questions we want to answer. So there's an asymmetry in this argument.
Take a thing that we're trying to understand down to the finest detail, and compare it to a caricature of some other thing that we're not trying to understand at such a fine resolution.
A common measure of complexity is the amount of information required to fully describe or recreate some system.
If you simply gather a very large number of hydrogen atoms into a region of space at a certain density, you will create star. From this angle, it isn't terribly complex.
The instructions for creating a cell from scratch are... immensely more complicated.
The star's behavior, .e.g. the movement and changes of the convection zones, fusion dynamics, how the magnetic fields change over time, coronal mass ejections, sunspots, etc. may be extremely complex. I think few people who know much about stars would disagree on that.
But I would wager there are many more orders of magnitude of complexity going on in a human cell, from an information theory perspective. Even just describing individual proteins themselves and how they fold is phenomenally difficult.
Of course, I may be wrong about the cell's behavior having higher complexity. The important take away is that it is possible to make such comparisons in a meaningful way.
Good points, but there's still something missing in the comparison. It's the difference between the initial information content, and the dynamics. Suppose we had to fix some problem in a star such that we need to precisely manipulate the magnetic fields, and perhaps things at a quantum scale. At that point, we are concerned with the fine-scale configuration of that particular star. Your proposed star creation algorithm only gives an ensemble over all stars of that particular mass and initial composition. It has less information content, because it doesn't create a particular star. I.e. we are willing to accept a huge class of individuals that we call "stars".
So, we're back to comparing thing A that we need to understand at the finest scale, to thing B where we ignore its individual complexity in favour of the stereotypical version. It's easy to estimate the gravitational attraction or mass of a cell. It's this fine-scale manipulation that causes these severe requirements for deep understanding.
EDIT> :) The instructions for creating life are even simpler. 1) Have a Big Bang. 2) Wait.
Hmm. You are making me think hard, which I like. Given that any human description of a system is going to be an approximation of reality, I suppose the one of the key difficulties is determining which aspects of the system are more important for our model to more closely match.
Even if the information theory metric of complexity is somewhat flawed, given our limitations, I think it is a useful tool. I'm not sure what would be a better way of comparing complexity.
At the very least, I think I can make statements such as: "a closed container of hydrogen gas at room temperature and pressure is a much simpler system than a Swiss watch", which we could roughly quantify in a somewhat robust way. The hydrogen part is easy, as the atoms are indistinguishable, and their movements can be closely approximated with simple formulas.
P.S. I just remembered a good (and short) minutephysics video on entropy & complexity, perhaps it is worth linking: https://youtu.be/MTFY0H4EZx4
Is it possible that no individual star OR individual cell can be sufficiently described because of quantum uncertainty effects that would affect any "object" with electrons (speaking as a biologist; not a physicist).
Also: this is a really great, really stellar thread.
Not sure how electrons enter into it. Quantum Mechanics (QM) isn't limited to electrons. Chemistry is largely focused on electrons, so maybe that's where you were first introduced to QM?
cancer isn't a particular state, except in the vaguest sense of 'continually multiplying, but like, in a bad way'.
any person's cancer is millions/billions of semi-independent, extremely complicated, poorly understood state machines, with a variety of mutations, constantly interacting and evolving against any treatments applied and immune reactions.
imho, cancer is a fundamental disease/property of multicellular life, and trivial reductionist perspectives completely out of touch.
> imho, cancer is a fundamental disease/property of multicellular life
I like analogizing between multicellular organisms and nation-states, in that both are complex systems built upon the coordination of many individual systems (cells/people). In the case of cancer, what we have is essentially rebellion, a failure of control: individual cells decide to stop cooperating and instead begin competing with the body that houses them. So I agree with you... rebellion is always a threat to any system of control.
Unlike actual rebellion, though, there's no way the cancer can "win" in the sense of taking over control of the body. If only cancer could realize the futility of its crusade...
In principle it shouldn't matter that cancer is not well defined, if health is well defined. "Just" visit every single cell and repair its gene sequence to your body's consensus sequence, and similarly for the epigenetic state to the extent necessary -- the latter requires more knowledge to do correctly, but otoh seems less crucial.
This is of course ridiculously ambitious compared to the current state of the art, but I think it's a reasonable start to countering the claim that a general cure for cancer is impossible in principle.
A cell /is/ epigenetic state, and the effect of any piece of DNA is profoundly controlled by other pieces of DNA, RNA, proteins, RNAs interacting with RNAs, RNAs interacting with proteins, proteins interacting with proteins, etc. Scrubbing the proteins, RNA, and so forth from a cell without killing it is inconceivable.
That said, I don't want to say that cancer is fundamentally beyond us. I think cheap sequencing and emerging highly targeted DNA editing systems, along with better understanding of the immune response to cancer, will get us most of the way there in a practical sense.
Repairs of all these things are performed by the cell itself without killing itself, so they're surely physically possible. But they're limited by a lack of outside information -- e.g. if the DNA is too corrupt, the repair processes can't check the uncorrupted DNA of other cells. That could be fixed with advanced enough technology.
killing the cell is actually not a big deal, any given cell is generally replaceable.
What you suggest is more or less what I mention; you could, say, try to add back some genetic machinery for the cancer cells to recognize that they're defective, and then they kill themselves. Or help the higher level repair mechanism (the immune system) target cancer cells.
To my understanding, trying to fix anything at the level between whole cell and DNA mutation is much harder.
Yes, I'm not gonna pretend to know what avenues are promising or how long it'll take to invent -- maybe humans will go extinct or obsolete first. I just disagree with the article's pooh-poohing towards "why don't we include in our portfolio of bets some actually trying for a cure someday".
This argument doesn't follow. The fact that most multicellular organisms get some cancer yet organisms with quadrillions of cells exist is good evidence that cancer rates can be driven to arbitrarily small levels; there's no fundamental lower bound. In the ancestral environment, cancer rates are set by a resources trade-off, and, since we have vastly more resources, there's no a priori reason to think we can't drive the cancer rate vastly lower than today.
It's like arguing that entropy always increases and therefore fighting disease is fundamentally hopeless, or requires non-logical approaches. Yes, of course "ill health" can't be cured in general, but we can drive disease rates ever lower.
I agree in a long term sense (we'll figure it out eventually, and fuck evolution), but I don't think we can assume evolution leaves us in a situation where cancer is easy to solve, and we just need to tie off some loose ends, or turn up a few knobs. And I don't think the understanding of cancer levels in, say, whales is developed to do more than guess something is going on. Some theories suggest better repair mechanisms, others that it's simply different selective effects at the cellular level in larger organisms.
> I don't think we can assume evolution leaves us in a situation where cancer is easy to solve, and we just need to tie off some loose ends, or turn up a few knobs.
Sure, but no one disputes this. Silicon valley investing in cancer research does not imply anyone takes such a silly position.
Surprisingly, it isn't fundamental to multicellular life! Consider the naked mole rat. In decades of study, and exposure to mutagenic compounds, there are been only one or two documented cases of cancer in naked mole rats. The reason why isn't clear, but it shows that it is possible to dramatically reduce the prevalence of cancers of all kinds. I agree cancer can't be completely gotten rid of, but the likelihood of it can be reduced by orders of magnitude, and least in theory.
Chaotic, unpredictable behaviours can emerge when simpler, predictable elements are brought together. A double pendulum is a good example of this.
Agreed that we don't yet know how to regulate the apoptosis, or understand how metastasis works. DNA Methylation, small RNA regulation, and purpose of non-coding RNA isn't very well understood yet, too.
> I believe it's much easier to simply figure out the right cocktail that would change cancerous cells into normal cells again, and then find the delivery mechanism for that.
I reckon much of this has to do with small RNA and miRNA based regulation of transcription. Essentially the specific portions of the RNA/DNA are "silenced" by several regulatory factors. If a growth regulator gene, say CDKNA is accidentally silenced then the cell would undergo an uncontrolled growth, _with_ mutations. This in turn will grow "diseased" cells, eventually causing cancer. Trouble is, we just do not understand this properly, yet.
I have little doubt cancer will be someday as well. It might not -- probably won't -- happen in my lifetime. But if humanity hasn't collapsed, I find it very unlikely that we're still dealing with cancer in a thousand years.
>The universe is logical. Each cell in the human body is at its core just a very complex state machine.
Even if determinism holds (and, spoiler alert from about 1927, it doesn't), you can't avoid chaos. Lorenz found that out and defined Chaos: where the present determines the future, but the approximate present does not approximately determine the future.
I assure you, biological systems exhibit all the hallmarks of (possibly) deterministic mathematical chaos.
Gene Regulatory Network resembles (stochastic) recurrent neural network and is sometimes modeled as such. Each cell has it's own GRN and then there is signaling between the cells.
Its understandably very hard problem to nudge network states back to the normal or to kill itself once it's gone haywire and causes other networks go haywire too. The "error state" cells are changing and those who survive the last nudge continue to reproduce.
If I understand Kozubek's argument correctly, cancer is ecologic, not systemic because of this evolution of cancer cell populations. If the cancer is ecologic problem, solving cancer means that it's not enough to figure out cell's state and fix it. You must figure out how the cancer cell ecology works and find a way to drive it into extinction without survivals. Just setting more mousetraps is not working solution if the mouse population is evolving hour by hour and branching.
This doesn't mean the problem can't be solved by "logic". If true, then research groups that are operating within such misguided frameworks will need to update their understanding of how cancer works.
I think a common trope is to point out some system that humans are currently unable to model in a robust or effective manner, and then throw up one's hands and declare "science and logic can't be used to solve this problem!" The current lack of an effective model for some system in no way implies that one will not eventually be found.
To be fair, this article isn't quite doing that, and makes some very important points. I only bring this up as it is a misleading line of argument to watch out for that I run into from time to time, and a few lines in the article were slightly reminiscent of such reasoning.
Ecology is a scientific endeavor, and perhaps it will prove to be a more powerful paradigm for looking at a cancer. I hope we can make the most of any tools at our disposal to significantly reduce the harm caused by cancer.
>This doesn't mean the problem can't be solved by "logic".
That's not what the author was saying.
It's useless to judge articles based on their title or headline because they are either selected by editor or there are multiple titles and A/B testing is used to find one that gets most clicks.
It seems that most comments are just comments based on the headline.
we need to consider that the system of cancer goes far beyond the biochemistry of cancer cells. Cancer relates to our fundamental constitution as multicellular organisms, our limited lifespan, the epidemiology of the aging population, socioeconomics and the future of society. Those who believe that the problem of cancer can be solved by killing or reprogramming cancer cells need to take a step back from the molecular technicalities and take a look at the bigger picture.
How cancer fits into the evolutionary context is obviously important to understand, but the author's conclusion is unfounded. Cancer rates in the ancestral environment is set by a balance between costs and benefits of anti-cancer mechanism. But we are not in the ancestral environment, and there's no a priori reason (Darwinian, thermodynamic, or otherwise) to think that cancer rates couldn't be driven down to negligible rates given our much greater resources.
I think I understand the author's point, but just as people here are making sweeping statements about biology, he seems to have some minor misconceptions about technology.
Let's take a step back ... my understanding of what the author's saying is that "solving" cancer is no easier in some sense than "solving" biology.
Yes, we have to think of cancer as some kind of adversarial game -- it's not enough to solve a snap-shot of that game. But ... that doesn't mean that we can't have active defences that work for the vast majority of people. It's just that maybe we need to know how to build people from molecules, first.
I think we'll solve biology in the sense of being able to engineer life from first-principles. I make no predictions on time-frame.
There are no monstrously hard computational power problems in drug development that are waiting for mathematical brains to pursue. There are hard Empirical problems. Empirical problems are problems which require actual experiments to show resultant data.
> There are no monstrously hard computational power problems in drug development that are waiting for mathematical brains to pursue
Not sure if I would put it that way. For ex, in principle, you could use molecular dynamics and search to find protein sequences that form other proteins/antibodies that can hit targets you want or operate in a more complex fashion. So hard computational power can most definitely help out (and depending on level of advance, help out a great deal). Ofc that doesn't mean you don't need experiments at all.
My understanding of this argument is that because of cancers many and possibly infinite forms there is no 'cure for cancer'. While I can appreciate the mathematical correctness of this point (sure did take a long article to get this across), it seems largely to miss the point. If cancer rates become low enough that they only kick in at 120 and that people begin dying of other things, whether a small group of people continue to die of cancer vs the rates today is effectively curing cancer, even if its not entirely complete.
Another example of why this sort of thinking is missing the bigger picture - many people today die not because we don't know how to treat something, but instead because they can't afford the treatment.
A) cancer cells constitute a separate species, or at least evolutionary "actor".
B) the tech naivity is not that things can't be deeply understood, but that it's a moving target, and less than complete erradication of the parasite just increases evolutionary pressure leading to decreased understanding of the foe.
I'm not sure what the point of this essay is supposed to be. Should we ignore promising avenues of cancer treatment research just because they won't work in all cases or for all cancers, or because the person cured is just going to die of something else later?
Science an empirical endeavor. The world determines what is, not logic, or math. Logic and math are great tools for making sense of observations, but they do not determine what will be observed. Otherwise, there would have been no need to carry out experiments. People, armed with only logic, could have deduced any truths about the world from their arm chairs.
Some, like Aristotle, did try to do that. To be fair, it was a mix of observation and first principles, but it was lacking adequate experimentation, as humans later found out.
> People, armed with only logic, could have deduced any truths about the world from their arm chairs.
Fair enough. I'm probably giving too much of my own spin to the word "logic".
I'm thinking of logic as being somewhat grounded in empirical observations. I agree that armchair logic completely removed from reality is of questionable value.
At this stage of my understanding, I would argue that our notion of logic and math largely stems from us creating models about the world that lead to abstract deductions, which often are eventually used in new models about the world... and so on. This cycle probably got started as early humans acquired better mental models for categorizing objects of different types and their apparent boundaries, and then began to "count" like entities.
If math wasn't useful for describing the world, I doubt we would have done much with it.
Cancer, like aging, is an example where much of the research community is undertaking very challenging and expensive work with marginal expectation value because that dovetails well with the types of fundamental research that can be funded, not because of any expectation that it is the best approach with the highest expectation value. This is an age of genetics, genetics is popular, and so people are getting funded for personalized medicine and ever more intricate mapping of cellular biology.
But there are hundreds of types of cancer, and taking the genetics/drug discovery approach for each of them is its own distinct and massively expensive undertaking. It'll never get done: the research community and its funding sources are not large enough to make significant progress on the whole of the problem in the next few decades. This isn't hacking cancer, this is hacking the cancer funding institutions in order to obtain funding to get on with the fundamental life science research goal of mapping all of cellular metabolism. Cancer is the excuse, but not the goal.
This is a cultural problem.
Hacking cancer would be to sit down and say, ok, the economics of this are not working, we need to find common points to target, a way to produce a universal cancer therapy at no greater expense than one of these single cancer therapies.
Some immunotherapies, like CAR-T approaches, are a small step in this direction, something that can be applied to multiple cancers with a lower cost of customization per cancer type.
The best target, however, is to block telomere lengthening; disabling both telomerase and alternative lengthening of telomere (ALT) mechanisms. This is a small area of biochemistry in comparison to the scope of most single cancer explorations. All cancers depend on telomerase or ALT or both. All of them. No exceptions. No cancer can evolve its way around a suppression of these mechanisms. It will simply die, losing its ability to replicate uncontrollably. Some noted research groups are making early inroads into disabling telomerase in a targeted way. ALT remains to be dealt with, but is easier to work with than telomerase interdiction by virtue of the fact that ALT doesn't happen in normal cells.
A telomere lengthening interdiction treatment would be applicable to all cancers, and it doesn't appear to be more expensive to develop than any other approach to a specific cancer. That is what hacking cancer research looks like; identifying a way to completely change the economics of the situation, and redirect the primary effort back to producing an effective cures as soon as possible.
Lastly, I have to fundamentally disagree with the final lines of this article; cancer can absolutely be dealt with robustly by killing cancer cells. You just need to be selective enough, early enough, and comprehensive enough, and raising the bar on these items is the whole point of the field.
> Andy Grove has had prostate cancer, and now suffers from Parkinson’s, so it’s no wonder that he’s taken aback at how poorly we understand each of those diseases – not to mention all the rest of them. But his experience in the technology world has warped his worldview. We are not suffering from a lack of urgency over here – talk to anyone who’s working for a small company shoveling its cash into the furnace quarter by quarter, or for a large one watching its most lucrative patents inexorably melt away. And we don’t suffer from a lack of hard-charging modern management techniques, that’s for sure.
What we suffer from is working on some of the hardest scientific problems in the history of the species.