The Cancer Resolution?

post by PeterMcCluskey · 2024-07-24T00:25:17.322Z · LW · GW · 24 comments

This is a link post for https://bayesianinvestor.com/blog/index.php/2024/07/23/the-cancer-resolution/

Contents

  Older Theories
  Evidence Discrediting the DNA Theory
  Evidence of Fungi
  Medical Establishment Inertia
  Many Cancers?
  Implications for Treatment
  Concluding Thoughts
None
24 comments

Book review: The Cancer Resolution?: Cancer reinterpreted through another lens, by Mark Lintern.

In the grand tradition of outsiders overturning scientific paradigms, this book proposes a bold new theory: cancer isn't a cellular malfunction, but a fungal invasion.

Lintern spends too many pages railing against the medical establishment, which feels more like ax-grinding than science. I mostly agreed with his conclusions here, but mostly for somewhat different reasons than the ones he provides.

If you can push through this preamble, you'll find a treasure trove of scientific intrigue.

Lintern's central claim is that fungal infections, not genetic mutations, are the primary cause of cancer. He dubs this the "Cell Suppression theory," painting a picture of fungi as cellular puppet masters, manipulating our cells for their own nefarious ends. This part sounds much more like classical science, backed by hundreds of quotes from peer-reviewed literature.

Those quotes provide extensive evidence that Lintern's theory predicts dozens of cancer features better than do the established theories.

Older Theories

  1. The DNA Theory (aka Somatic Mutation Theory): The reigning heavyweight, this theory posits that cancer results from an accumulation of genetic mutations in critical genes that control cell growth, division, and death.

  2. Another old theory that still has advocates is the Metabolic Theory. This theory suggests that cancer is primarily a metabolic disease, characterized by impaired cellular energy production (the Warburg effect). It proposes that damage to mitochondria is a key factor in cancer development. I wrote a mixed review of a book about it.

Lintern points out evidence that mitochondria are turned off by signals, not damaged. He also notes that tumors with malfunctioning mitochondria are relatively benign.

Evidence Discrediting the DNA Theory

The standard version of the DNA Theory predicts that all cancer cells will have mutations that affect replication, apoptosis, etc.

Around 2008 to 2013, substantial genetic data became available for cancer cells. Lintern wants us to believe that this evidence fully discredits the DNA Theory.

The actual evidence seems more complex than Lintern indicates.

The strongest evidence is that they found cancers that seem to have no mutations. [Updated 2024-07-25: DirectedEvolution suggests [LW(p) · GW(p)] that this evidence isn't very strong.]

Almost as important is that the mutations that are found seem more randomly distributed than would be expected if they caused consistent types of malfunctions.

Lintern's theory seems to explain all of the Hallmarks of Cancer, as well as a few dozen other features that seem to occur in all cancers.

He argues that the DNA Theory does a poor job of explaining the hallmarks. DNA Theorists likely reject that characterization. They appear to have thought their theory explained the hallmarks back before the genetic data became available (mostly just positing mutations for each hallmark?). My guess is that they are busy adding epicycles to their theory, but the situation is complex enough that I'm having trouble evaluating it.

He also points out that the DNA Theory struggles with Peto's Paradox (why don't larger animals get more cancer?), while his theory neatly sidesteps this issue.

Additionally, mouse embryos formed from cancer cells showed no signs of cancer.

Evidence of Fungi

A key game-changer is the growing evidence of fungi in tumors. Until 2017, tumors were thought to be microbe-free. Now? We're finding fungi in all types of cancer, with tumor-specific fungal profiles.

There's even talk of using fungal DNA signatures to distinguish cancer patients from healthy individuals.

It's not a slam dunk for Lintern's theory, but it shifts the odds significantly.

Medical Establishment Inertia

It looks like people in the medical mainstream respond respectfully to the ideas in the book, when they react at all. Yet the DNA Theory seems to remain the prevailing dogma. The shortage of reactions to Lintern is disappointing.

My impression is that researchers are hedging their bets when they can conveniently do so, but many of them have built careers that depend on the DNA Theory.

It's possible that some important parts of the establishment are pivoting their research in the directions that Lintern suggests, and are being quiet until they have something worth publishing.

It seems likely that some parts of the establishment are treating the DNA Theory as a religion rather than a theory. I can't tell how widespread that problem is.

Possibly some apathy toward fungal infections is because solutions are somewhat less likely to involve patentable treatments. But there's still some room for patenting new anti-fungals, so I doubt that this is the primary obstacle to accepting Lintern's theory.

Paul Ewald's book Plague Time anticipated some of Lintern's claims, arguing that pathogens are the root cause of many chronic diseases. It was published in 2000, and overlooks fungi (little of Lintern's evidence was available then). Ewald's reasoning is more theoretical than Lintern's.

My limited attempt to spread Ewald's theory stopped when someone pointed to evidence that mice raised in a sterile environment developed most of the same chronic diseases. Lintern counters that there are many microbes that aren't detected by the tests that supposedly confirmed that the mice were microbe-free, so we should wonder whether the experiments demonstrated much. I feel foolish for not wondering about that 20+ years ago.

This reminds me of how long it took to refute the theory of spontaneous generation, due to mistaken beliefs about what it took to create a sterile environment.

Lintern reports that fungal infections have also been implicated in Parkinson's disease and multiple sclerosis, yet many sources still say we don't know the causes of those diseases. Is there a pattern here?

I often say to myself that much of the medical establishment acts as if they believe our bodies are the result of semi-intelligent design rather than evolution. E.g. their disinterest in a paleo diet. This book reinforced that impression.

Experimental History has some relevant comments about the state of cancer research.

Many Cancers?

Maybe parts of the medical establishment have rejected the whole idea of a theory of cancer.

Researchers who try to take the DNA Theory seriously end up confused by the variety of different mutations that they end up studying. This focus makes it hard to see the similarities between tumors.

I've seen many denials that cancer is a single disease. I see a good deal of tension between those denials and the DNA Theory. And don't the Hallmarks of Cancer point to it being a single disease?

Ironically, Lintern advocates a single-disease model, even though his theory implies that a wide range of different fungi are responsible. Presumably many different anti-fungals are needed for the different types of fungi. So in some sense the many-cancers view is likely to be partly correct.

Implications for Treatment

Lintern doesn't offer much hope for reliable cures. He offers many somewhat new ideas for treatments that will sometimes work. The most obvious ones are anti-fungal drugs.

Progress at treating diseases that are known to be fungal infections may be a bit better than progress at curing cancer, but deaths from fungal infections have still been increasing.

Much of Lintern's advice for people who have cancer now consists of standard recommendations to adopt a healthy lifestyle. That shouldn't be surprising: if most chronic diseases are due to pathogens, there will be plenty of overlap in strategies for fighting them.

That includes a long section on the benefits of organic food. I was unimpressed by how it started, with a correlational study that likely had confounders that couldn't reasonably be controlled for. But he made up for that by explaining several causal models that I hadn't previously considered.

E.g. fungicides. Indiscriminate use of fungicides on non-organic crops means that there are fewer beneficial fungi which provide nutrients to the plant, leading the plant to have less nutritional value. More importantly, plants defend themselves against fungi, similar to the fungi that endanger us, by generating anti-fungal compounds that are well targeted against those fungi. Organic foods have more of those anti-fungals, because they're produced in reaction to fungal attacks. Those anti-fungals sometimes work in our bodies when we eat them.

I ended up deciding to give slightly higher priority to buying organic food.

Lintern suggests that chemotherapy is generally a bad idea. One clear reason is that it damages the immune system, and the immune system is the main defense against additional cancers. But he still supports it in cases where it shrinks the tumor enough to enable surgery. I continue to be concerned about how hard it would be to evaluate a doctor's recommendation to get chemotherapy.

What does Lintern's theory mean for Aubrey de Grey's proposed cure for cancer (WILT)? That looks much less promising now. WILT no longer looks like it addresses the root cause of cancer. Even if Lintern's theory is somewhat wrong, cancer stem cells now seem much more important than regular cancer cells as a source of excessive cell replication. Cancer stem cells don't depend on telomerase in the way that other cells do. It looks like Aubrey has a new version WILT 2.0 which does something to address cancer stem cells. What little I understand of it leaves me skeptical.

The good news is that cancer rates can likely be reduced to roughly the rates seen in young adults if other parts of Aubrey's plan work, particularly the parts that affect the immune system.

Concluding Thoughts

There's actually an important similarity between the DNA Theory and Lintern's theory. In both, eukaryotic cells have evolved to serve their own interests, in ways that conflict with the host's interests. The key difference is when that evolution started: years before the cancer was detected, or millions of years?

Evolutionary theory should create a moderate presumption that hostile organisms do more harm to our bodies than do mistakes.

Lintern's theory seems to have more explanatory power than any other theory.

Whether or not Lintern is entirely correct, his work highlights two crucial points:

  1. We shouldn't demand that all proposed cancer treatments conform to the DNA Theory.

  2. We need to rethink how we evaluate the effectiveness of cancer treatments. There's large room for improvement in the choice of criteria without adopting a strong opinion on which theory of cancer is correct. The evidence concerning cancer stem cells seems like a strong argument against relying on tumor shrinkage as evidence of success.

At one level, scientists have failed badly at explaining cancer, and it seems like only an outsider was able to point out that the emperor has no clothes.

But that's at the level of broad theory. At the level of small experiments, the medical establishment has been diligently uncovering plenty of evidence to reject the DNA Theory and to focus some attention on pathogens.

The book isn't as professionally written as I'd like. E.g. he sometimes cites news stories instead of the peer-reviewed papers on which the stories are based.

Parts of the book are difficult to read. Most people should feel free to skip parts of the book, mainly after page 250.

H/T Dave Asprey.

24 comments

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comment by DirectedEvolution (AllAmericanBreakfast) · 2024-07-25T15:48:07.492Z · LW(p) · GW(p)

Fungal infections are clearly associated with cancer. There's some research into its possible carcinogenic role in at least some cancers. There's a strong consensus that certain viruses can, but usually don't, cause cancer. Personally, it seems like a perfectly reasonable hypothesis that fungal infections can play an interactive causal role in driving some cancers.  In general, the consensus is you typically need at least two breakdowns of the numerous mechanisms that regulate the cell cycle and cell death for cancer to occur.

I'm a PhD student in the cancer space, focusing on epigenetics and cancer. Basically, this is the field where we try to explain both normal cellular diversity (where DNA mutations are definitely not the cause except in very specialized contexts like V(D)J recombination) and cancers apparently not driven by somatic mutations in protein-coding genes.

Mutations not in protein-coding genes are not necessarily inert. RNA can be biologically active. Noncoding DNA serves as docking sites for proteins, which can then go on to affect transcription of genes into mRNA. The proteome can also be affected by alternative splicing of mRNA. Non-coding mutations can potentially affect any of these processes and thereby affect the RNA and protein landscape within a cell.

In 2024, our ability to detect mutations varies widely across the genome, due both to the way we obtain sequencing data in the first place and the way we attempt to make sense of it. NGS sequencing involves breaking the genome into short fragments and reading around 150 base pairs on either end of the fragments, then trying to map it back to a reference genome. Mapping quality will suffer or completely degrade both if the patient has substantial genetic difference from the reference genome or in regions that are highly repetitive within the genome, such as centromeres. When I work with genetic data, there are regions spanning multiple megabasis that are completely blank, and a large percentage of our reads have to be thrown out because we can't unambiguously map them to a particular location on the genome. This will be partially overcome in the future as we start to use more long-read sequencing, but this technology is still in its early stages and I'm not sure it will completely replace NGS for the foreseeable future.

In the epigenetics space, we focus on several aspects of cell biochemistry apart from DNA mutations. The classic example is DNA methylation, which is a methyl group (basically a carbon atom) present on about 60% of cytosines (C) that are immediately followed by guanine (G). The CpG dinucleotide is heavily underrepresented relative to what you'd expect by chance, and its heavily clustered in gene promoters. Methylated CpG islands in promoters are associated with "off genes". The methylation mark is preserved across mitosis. It's thought to be a key mechanism by which cell differentiation is controlled. We also study things like chromatin accessibility (whether DNA is tightly packaged up and relatively inaccessible to protein interactions or loose and open) and chromatin conformation (the 3D structure of DNA, which can control things like subregion localization into a particular biochemical gradient or adjacency of protein-docking DNA regions to gene promoters).

These epigenetic alterations are also thought to be potentially oncogenic. Epigenetic alterations could potentially occur entirely due to random events localized to the cell in which the alterations occur, or could be influenced by intercellular signaling, physical forces, or, yes, infection. If fungal infections control cells like puppets and somehow cause cancer, my guess is that it would be through some sort of epigenetic mechanism (I don't know if there are any known fungi that can transmit their DNA to human cells).

Epigenetics research is mainstream, but the technology and data analysis is comparatively immature. One of the reasons it's not more common is that it's much harder to gather data on and interpret than it is to study DNA mutations. Most of our epigenetics methods involve sequencing DNA that has undergone some extra-fancy processing of one kind or another, so it's bound to be strictly more expensive and difficult to execute than plain ol' DNA sequencing alone. Compounding this, the epigenetic effects we're interested in are typically different from cell to cell, meaning that not only do you have these extra-challenging assays, you also need to aim for single-cell resolution, which is also either extremely expensive (like $30/cell, isolating individual nuclei using a cell sorter and running reactions on each individually, leading to assays that can cost millions of dollars to produce) or difficult (like using a hyperactive transposase to insert DNA barcodes into intact nuclei that give a cell-specific label the genetic fragments originating from each cell, bringing assay costs down to a mere $50,000-$100,000 driven mainly by DNA sequencing rather than cell processing costs). This data is then very sparse (because there's a finite amount of genetic information in each cell), very large, and very difficult to interpret. We also have extremely limited technologies to cause specific epigenetic changes, whereas we have a wide variety of tools for precisely editing DNA.

For potentially oncogenic infections, fungal or otherwise, you'd want to show things like:

  • We can give organisms cancer by transferring the pathogen to them
  • We can slow or prevent cancer by suppressing the putatively oncogenic pathogen.
  • The pathogen is found in cancer biosamples at an elevated rate
  • There are differences between the cancer-associated pathogens and non-cancer-associated pathogens, or cellular changes that make them more susceptible to oncogenesis through their interactions with the pathogen

All of this seems like a perfectly respectable research project, just difficult. I can't imagine anybody I work with having a problem with it. Where they probably would have a problem would be if the argument was that "fungal infections are the sole cause of cancer, and DNA mutations or epigenetic alterations are completely irrelevant to oncogenesis."

There's an angle I've neglected in this post until now, which is the perspective from evolutionary theory. it's more common to refer to this in explaining how cancer evolves within an individual. But it's also relevant to consider how it bears on the Peto paradox. Loosely, species tend to evolve such that causes of reproductive unfitness (including death) tend to balance out in terms of when they occur in the life cycle. Imagine a species under evolutionary pressure to grow larger, perhaps because it will allow it to escape predation or access a new food source. If the larger number of cells put it at increased risk of cancer, then at some point there would be an equilibrium where the benefit of increased size was cancelled by the cost of increased oncogenesis risk. This also increases adaptive pressure to stabilize new oncopreventative mechanisms in the population that weren't present before. This may facilitate additional growth to a new equilibrium.

This helps explain why cancer isn't associated with larger size: adaptive pressure to develop new oncopreventative mechanisms increases in proportion to the risk to reproductive fitness posed by cancer.

Replies from: PeterMcCluskey
comment by PeterMcCluskey · 2024-07-25T19:00:45.002Z · LW(p) · GW(p)

Thanks. You've convinced me that Lintern overstates the evidence of mutation-free cancer cells.

comment by localdeity · 2024-07-24T02:33:21.225Z · LW(p) · GW(p)

My first significant thought (which came up a bit in the AIs' output) is that it would seem that, if fungi cause cancer, then the fungi would at least sometimes be transmitted from one person to another, and if you weren't aware of the fungi, then this would look like cancer being transmitted from one to the other.  Yet I think this has basically never been observed.[1]

One could try supposing that each fungus is only rarely able to infect people—only the few individuals that are unusually vulnerable to it.  But, well.  I imagine that would generally include anyone whose immune system is crippled.  Surely there have been enough cases of people with cancer next to old, immunocompromised people in a hospital, with sufficient mistakes in hygiene that the one would have infected the other.  Maybe there are additional requirements for an individual to be infected (the fungus has a favorite temperature? Acidity? Salt level?)... but even taking that into account, I think there should have been enough cases that we would have noticed.  (If the chance of an individual being infectable by a given fungus is so low that we never see transmission, then how is it that, er, 1/6th of all deaths are caused by cancer?  There would have to be zillions of different fungi, each of which is able to infect only a tiny number of people... which surely would have led to natural selection for much better infectivity by now?)

Incidentally, I think it is known that there are some viruses (like HPV) that cause (or greatly heighten the risk of) cancer.  It's plausible that fungi play a significantly larger role of this type than people realize.  But for it to be the primary cause seems implausible.

The strongest evidence is that they found cancers that seem to have no mutations.

This seems worth digging into.

  1. ^

    There are a few cases of cancers where it's known that the actual cancer cells themselves go from organism to organism: https://en.wikipedia.org/wiki/Clonally_transmissible_cancer 

Replies from: PeterMcCluskey
comment by PeterMcCluskey · 2024-07-24T02:52:10.526Z · LW(p) · GW(p)

How would transmission be detected? It probably takes years before a tumor grows big enough for normal methods to detect it.

I assume that transmission is common, mild infections are common, and they rarely become harmful tumors.

Replies from: localdeity, Linch
comment by localdeity · 2024-07-24T03:27:46.805Z · LW(p) · GW(p)

It probably takes years before a tumor grows big enough for normal methods to detect it.

There exist fast-growing cancers.  I figure that if the fungi theory is correct, then probably a good amount of this is caused by the specific fungus (and perhaps what part of the body that fungus targets), and most of the rest comes from the target's immune system (not sure what else would contribute significantly).  If transmission and mild infections are common, and if, say, 1% of cancers are fast-growing, I feel like there should be lots of cases where an immunocompromised person picks up a fast-growing cancer fungus at a hospital or something and, within a few years, gets diagnosable cancer.  Enough that it should have been noticed.  I don't have numbers for this, but that's my suspicion.

Or, for example... How often do couples get the same type of cancer?  I found this:

METHODS

The authors identified 25,670 cancer-free married couples in northern California who were followed for up to 31 years for the development of cancer. In Cox proportional hazards analysis, the development of cancer in a spouse was treated as a time-dependent, independent variable, and spouse-with/spouse-without risk ratios were determined, controlling for age and gender. For selected concordant espoused pairs, additional explanatory information was sought in their medical records.

RESULTS

There was no excess concordance for all cancers combined; the spouse-with/spouse-without risk ratio was 0.97 (95% confidence interval, 0.90–1.05). Statistically significant husband-wife associations were found only for cancer of the tongue and stomach and for non-Hodgkin lymphoma. Except for cancer of the penis/endometrium and testis/vulva, based on one couple with each combination, gender specific cancers did not aggregate within married couples. Established and suspected risk factors, not necessarily related to the marriage, were found for some individuals who had concordance with their spouses.

CONCLUSIONS

Little spousal concordance for cancer occurrence was found. The study of spousal aggregation does not appear useful in identifying unsuspected environmental causes of cancer in heterogeneous populations in urban areas of affluent Western countries. A cohort study would have to be much larger than this one to detect weak spousal concordance reliably..

Also, for whatever Claude's opinion is worth:

Q: How often do couples get the same type of cancer?

While it's not extremely common for couples to get the same type of cancer, it does happen occasionally. This phenomenon has been studied, and there are several factors to consider:

  1. Shared environmental factors: Couples often share the same living environment, diet, and lifestyle habits, which can expose them to similar cancer risk factors.
  2. Similar behaviors: Shared behaviors like smoking, alcohol consumption, or sun exposure can increase risk for certain cancers in both partners.
  3. Infectious agents: Some cancers are caused by infectious agents (like HPV for cervical cancer), which can be transmitted between partners.
  4. Age-related risks: As couples age together, they may face similar age-related cancer risks.
  5. Genetic factors: While not directly shared between couples, people might choose partners with similar genetic backgrounds, potentially influencing cancer risk.
  6. Coincidence: Given the prevalence of cancer, some couples will develop the same cancer by chance.
  7. Screening effect: When one partner is diagnosed, the other may be more likely to get screened, potentially leading to a diagnosis of a cancer that might have otherwise gone undetected.

Studies on this topic have shown:

  • A slight increase in cancer risk for partners of cancer patients, but this varies by cancer type.
  • Higher correlations for smoking-related cancers, suggesting shared lifestyle factors play a role.
  • Increased risk for cancers with infectious causes, like stomach cancer (H. pylori) or liver cancer (hepatitis viruses).

It's important to note that while interesting, these occurrences are not common enough to be considered a significant public health concern.

Replies from: PeterMcCluskey
comment by PeterMcCluskey · 2024-07-24T15:56:52.076Z · LW(p) · GW(p)

Enough that it should have been noticed.

My guess is that almost nobody looks for this kind of connection.

Even if they do notice it, they likely conclude that pathogens are just another small influence on cancer risk.

comment by Linch · 2024-07-26T20:10:31.017Z · LW(p) · GW(p)

Genes vs environment seems like an obvious thing to track. Most people in most places don't move around that much (unlike many members of our community) so if cancers are contagious for many cancers, especially rarer ones, you'd expect to see strong regional correlations (likely stronger than genetic correlations). 

Replies from: PeterMcCluskey
comment by PeterMcCluskey · 2024-07-28T02:40:20.277Z · LW(p) · GW(p)

Maybe? It doesn't seem very common for infectious diseases to remain in one area. It depends a lot on how they are transmitted. It's also not unusual for a non-infectious disease to have significant geographical patterns. There are cancers which are concentrated in particular areas, but there seem to be guesses for those patterns that don't depend on fungal infections.

comment by J Bostock (Jemist) · 2024-07-24T19:26:47.657Z · LW(p) · GW(p)

If you're willing to take my rude and unfiltered response (and not complain about it) here it is:

 This is very fucking stupid.

Otherwise (written in about half an hour):

  1. Fungal infections would lead to the vast majority of cancers being in skin, gut, lung i.e. exposed tissue. These are relatively common, but this does not explain the high prevalence of breast and prostate cancers. It also doesn't explain why different cancers have such different prognoses, etc.
  2. Why do different cancer subtypes change in prevalence over the course of a person's life if they're tied to infection?
    https://www.cancerresearchuk.org/health-professional/cancer-statistics/incidence/age#heading-One
  3. Around half of cancers have a mutation in p53, which is involved in preserving the genome. Elephants have multiple copies of p53 and very rarely get cancer. People with de novo mutations in p53 get loads of cancer. The random spread of DNA damage is downstream of the DNA damage causing cancer: once p53 is deactivated (or the genome is otherwise unguarded) mutations can accumulate all over the genome, drowning out the causal ones.
    https://en.wikipedia.org/wiki/P53
  4. If it was infection-based, then you'd expect immunocompromised patients to get more of the common types of cancer. Instead they get super weird exotic cancers not found in people with normal immune systems.
    https://www.hopkinsmedicine.org/health/conditions-and-diseases/hiv-and-aids/aidsrelated-malignancies
  5. Chemotherapy, does work? I don't know what to say on this one, chemotherapy works, are all the RCTs which show it works supposed to be fake? Do I need to cite them:
    https://pubmed.ncbi.nlm.nih.gov/30629708/
    https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)00285-4/fulltext
    https://www.redjournal.org/article/S0360-3016(07)00996-0/fulltext
    I feel like a post which uncritically repeats someone's recommendation to not take chemotherapy has the potential to harm readers. You should at least add an epistemic status warning readers they might become stupider reading this.
  6. Antifungals are relatively easy to get ahold of. Why hasn't this man managed to run a single successful trial? Moreover, cryptococcal meningitis is a fungal diseas which is fatal if untreated and, from the CDC:
    Each year, an estimated 152,000 cases of cryptococcal meningitis occur among people living with HIV worldwide. Among those cases, an estimated 112,000 deaths occur, the majority of which occur in sub-Saharan Africa.
    Which implies 40,000 people are successfully treated with strong antifungals every single year. These are HIV patients, who are more likely to get cancer and under this theory would be more likely than anyone else to have fungal-induced cancer. How come nobody has pointed out the miraculous curing of hundreds or thousands of patients by now?
  7. Scientific consensus is an extremely powerful tool.
    https://slatestarcodex.com/2017/04/17/learning-to-love-scientific-consensus/

I think the fungal theory is basically completely wrong. Perhaps some obscure couple of percent of cancers are caused by fungi. I cannot disprove this, though I think it's very unlikely.

Replies from: Armand_Cognetta
comment by Armand_Cognetta · 2024-07-25T15:09:04.036Z · LW(p) · GW(p)

+1000

It’s certainly possible that a small subset of cancers are caused/initiated by a fungal infection, but it’s extremely unlikely that our basic understanding of what causes most cancer is wrong at this point.

Also an interesting recent paper showing the potential for cancer to be driven by epigenetically (rather than through direct DNA mutations).

https://www.nature.com/articles/s41586-024-07328-w

Replies from: Jemist
comment by J Bostock (Jemist) · 2024-07-25T16:53:32.259Z · LW(p) · GW(p)

Epigenetic cancers are super interesting, thanks for adding this! I vaguely remember hearing that there were some incredibly promising treatments for them, though I've not heard anything for the past five or ten years on that. Importantly for this post, they also fill out the (rare!) examples of mutation-free cancers that we've seen, while fitting comfortably within the DNA paradigm.

comment by Ben (ben-lang) · 2024-07-24T10:58:39.066Z · LW(p) · GW(p)

Very interesting. Thank you for sharing this theory.

I had two thoughts. The first is: "Doesn't radiation cause cancer? Isn't this effect well established with evidence?". Because if radiation does cause cancer then that is strong evidence that the DNA theory is true of at least some cancers. (Because radiation cannot spread a fungus).

My second thought (which I agree is in some tension with the radiation one), is that, even if I subscribe to a DNA theory of cancer, I don't have to imagine that every tumour has a mutation (relative to the rest of the organism), or that tumour cells are unable to produce healthy embryos without a cancer. To use a software analogy, lets imagine we have a piece of software with a bug. We have all played a computer game where things are basically fine but there is that one time you ended up halfway inside a wall because of some collision error thing. You never worked out quite what did it that time, but the game was usually fine.

When a piece of software shows that collision bug, we don't need to assume that a cosmic ray has flipped a bit in the software. We can check that the code is the same before and after we saw the collision error. This doesn't mean we are going to see collision errors every single time we play that computer game, it just means that the game has a bug that can appear in some limited situations. Similarly, I can imagine that many organisms contain "bugs" in their DNA (the DNA they were born with, undamaged) and that some of these bugs only express themselves rarely, when specific circumstances arise, and sometimes the result of the "glitch" is cancer. In this model the tumours are not mutated. This model is consistent with the idea that radiation and so on can make cancer more likely, as flipping a bunch of bits in a piece of software is much more likely to introduce more bugs than to reduce the number. But it also seems consistent with some tumours being genetically identical to the rest of the organism. The main prediction of this sort of model would be a strong inherited tendency for certain cancers, especially for identical twins.

As a final thought. If the fungus theory is correct, it doesn't seem like it would be impossibly hard for someone to find some of the fungus cells in mouse A. Look at them under a microscope, "Yes, fungus all right." and then use them to give cancer to a bunch of other mice. So the fungus theory (unlike my speculations above) has the great advantage of seeming to be very testable.

Replies from: PeterMcCluskey
comment by PeterMcCluskey · 2024-07-24T15:48:41.484Z · LW(p) · GW(p)

Because radiation cannot spread a fungus

Anything that causes cell damage and inflammation has effects that sometimes make cells more vulnerable to pathogens.

comment by Yair Halberstadt (yair-halberstadt) · 2024-07-25T04:57:53.949Z · LW(p) · GW(p)

I want to take a look at the epistemics of this post, or rather, whether this post should have been written at all.

In 95% of cases someone tearing down the orthodoxy of a well established field is a crank. In another 4% of cases they raise some important points, but are largely wrong. In 1% of cases they are right and the orthodoxy has to be rewritten from scratch.

Now these 1% of cases are extremely important! It's understandable why the rationalist community, which has a healthy skepticism of orthodoxy would be interested in finding them. And this is probably a good thing.

But you have to have the expertise with which to do so. If you do not have an extremely solid grasp of cancer research, and you highlight a book like this, 95% of the time you are highlighting a crank, and that doesn't do anyone any good. From what I can make out from this post (and correct me if I'm wrong) you do not have any such expertise.

Now there are people on LessWrong who do have the necessary expertise, and I would value it if they were to either spend 10 seconds looking at the synopsis and saying "total nonsense, not even worth investigating" Vs "I'll delve into that when I get the time". But for anyone who doesn't have the expertise, your best bet is just to go with the orthodoxy. There's an infinite amount of bullshit to get through before you find the truth, and a book review of probable bullshit doesn't actually help anyone.

Replies from: yair-halberstadt
comment by Yair Halberstadt (yair-halberstadt) · 2024-07-25T05:03:52.475Z · LW(p) · GW(p)

Now it can be very frustrating to hear "you can't have an opinion on this because you're not an expert", and it sounds very similar to credentialism.

But it's not. If you'd demonstrated a mastery of the material, and came up with a convincing description of current evidence for the DNA theory and why you believe it's incorrect, evidence which is not pulled straight out of the book you're reviewing, I wouldn't care what your credentials are.

But you seem to have missed really obvious consequences of the fungi theory, like, "wouldn't it be infectious then", and all the stuff in J Bostock's excellent comment. At that point it seems like you've read a book by a probable crank, haven't even thought through the basic counterarguments, and are spreading it around despite it containing some potentially pretty dangerous advice like "don't do chemotherapy". This is not the sort of content I find valuable on LessWrong, so I heavily downvoted.

Replies from: PeterMcCluskey
comment by PeterMcCluskey · 2024-07-25T17:14:47.227Z · LW(p) · GW(p)

But you seem to have missed really obvious consequences of the fungi theory, like, "wouldn't it be infectious then",

I very much did not miss that.

containing some potentially pretty dangerous advice like "don't do chemotherapy".

Where did I say that?

Replies from: yair-halberstadt
comment by Yair Halberstadt (yair-halberstadt) · 2024-07-25T19:52:47.428Z · LW(p) · GW(p)

I very much did not miss that.

I would consider this one of the most central points to clarify, yet the OP doesn't discuss it at all, and your response to it being pointed out was 3 sentences, despite there being ample research on the topic which points strongly in the opposite direction.

Where did I say that?

I never said you said it, I said the book contains such advice:

Lintern suggests that chemotherapy is generally a bad idea.

comment by PeterMcCluskey · 2024-07-24T00:30:42.666Z · LW(p) · GW(p)

This comment describes some relevant research.

From Somatic Mutation Theory - Why it's Wrong for Most Cancers:

It should come as no surprise, therefore, that somatic mutations are questioned as representing "the" cause for the majority of cancers [10,11] and it should be noted that some cancers are not associated with any mutations whatsoever.

Importantly, a detailed analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies [48] revealed that "the vast majority, if not all, of aberrations that were observed in the cancer-affected cohort were also seen in cancer-free subjects, although at lower frequency" [47]. Thus, the notion that somatic mutations are necessarily harmful and can lead to cancer is not borne out by this study and further affirms the hypothesis that mutations observed in cancers are not the triggering event but more likely a means for the clonal replication of already transformed cancer cells.

From Speciation Theory of Carcinogenesis Explains Karyotypic Individuality and Long Latencies of Cancers:

However, despite 65 years of research on the mutation theory, there is still no proof for even one set of mutations that is able to convert a normal cell to a cancer cell.

Because the prevailing mutation theory has dominated the search for the genetic causes of cancer since the discovery of gene mutation in 1927 [111], consistent mutations or consistent karyotypic abnormalities with specific mutations were expected [15,21,22]. Instead, individual mutations [43,44] and individual karyotypes [2,9,112,113] were found, of which over 68,000 are listed in the NCI-Mitelman database of cancers [6].

The tissue organization field theory of cancer: A testable replacement for the somatic mutation theory

From Cancer Treatment: A Systems Approach

When the first results of The Cancer Genome Project were reported, many scientists were shocked to learn that most patients, including those with the same type of cancer, did not share the same cancer-related mutations.

The DNA Theory predicts that cancer will be more common in cells that replicate more frequently and/or in organs that have more cells. Lintern's theory suggests more cancer in organs that have more surface area that are accessible by fungi. I think the evidence favors Lintern here, but probably not very strongly.

Itraconazole therapy in a pancreatic adenocarcinoma patient: A case report: an example of a patient with a terminal cancer diagnosis recovering in apparent response to getting an anti-fungal drug.

Case studies with salvestrol treatment: a class of natural anti-fungals helped cure some "terminal" cancer patients. 6 more case studies. New clinical study with phytonutrients (phytoalexins) a randomized controlled trial.

Fungal diseases mimicking primary lung cancer: radiologic--pathologic correlation: cancer and fungal infections look similar. Somehow, this is rarely taken as evidence that they're the same thing.

How a plant's anti-fungal defence may protect against cancer.

From Finding the "Missing 50%" of Invasive Candidiasis:

Blood cultures are limited for diagnosing invasive candidiasis by poor sensitivity and slow turn-around time.

Replies from: tailcalled
comment by tailcalled · 2024-07-29T09:07:29.415Z · LW(p) · GW(p)

Importantly, a detailed analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies [48] revealed that "the vast majority, if not all, of aberrations that were observed in the cancer-affected cohort were also seen in cancer-free subjects, although at lower frequency" [47]. Thus, the notion that somatic mutations are necessarily harmful and can lead to cancer is not borne out by this study and further affirms the hypothesis that mutations observed in cancers are not the triggering event but more likely a means for the clonal replication of already transformed cancer cells.

Isn't case-control GWAS the wrong tool for the job since it's blind to rare mutations? I'd compare a person's cancerous cells to their normal cells instead, though I'm not an expert so maybe there's a problem with this.

comment by tailcalled · 2024-07-27T17:02:31.098Z · LW(p) · GW(p)

Almost as important is that the mutations that are found seem more randomly distributed than would be expected if they caused consistent types of malfunctions.

Can you expand on this? I can't help but think of performance problems caused by software extensions as an analogy; these are often quite randomly distributed, with there being many different kinds of extensions that can cause program activity to expand uncontrolledly. Shouldn't we expect the same with mutations?

Replies from: PeterMcCluskey
comment by PeterMcCluskey · 2024-07-28T23:34:19.270Z · LW(p) · GW(p)

The beginning of this comment [LW(p) · GW(p)] is how Lintern expands on that claim. But it sounds like you have an objection that isn't well addressed there.

If cancer merely involved one bad feature, I could imagine software analogies that involved a large variety of mistakes producing that one bad feature.

The hallmarks of cancer indicate that all cancers have a number of bad features in common that look sufficiently unrelated to each other that it seems hard to imagine large sets of unrelated mutations all producing those same hallmarks. Lintern lists many other features that could be considered additional hallmarks.

When I try to imagine software problems that seem analogous to cancer, I come up with problems such as spam where there's an optimizer that's generating the problems.

I'm unclear whether you're imagining software problems that I haven't thought of, or whether you're modeling cancer differently from me.

comment by PeterMcCluskey · 2024-07-24T00:35:51.689Z · LW(p) · GW(p)

Here are some conversations that I had with AIs, mainly Claude 3.5 Sonnet:

Perplexity, in response to "arguments against Mark Lintern's theory that fungal infections are the primary cause of cancer?":

  1. Effectiveness of current treatments: Many existing cancer treatments that do not specifically target fungal infections have shown efficacy in treating various types of cancer, which may contradict the theory that fungi are the primary cause [1].

That stands out as strange. The "effectiveness" of current cancer treatments is what led me to search for what is wrong with cancer research.

me: What are the strongest arguments against Mark Lintern's claim that fungal infections are the primary cause of cancer?

Claude:

Mark Lintern's claim that fungal infections are the primary cause of cancer is not widely accepted in the scientific community. While it's important to consider alternative hypotheses, there are several strong arguments against this claim:

  1. Lack of robust scientific evidence: - There is a scarcity of peer-reviewed, well-designed studies supporting the fungal infection hypothesis as a primary cause of cancer. - The vast majority of cancer research points to genetic mutations, environmental factors, and other well-established risk factors.

  2. Inconsistency with epidemiological data: - Cancer incidence patterns and risk factors observed in large-scale population studies don't align well with patterns of fungal infections. - Known risk factors like smoking, UV radiation, and certain chemicals have much stronger correlations with cancer incidence.

  3. Cancer genomics: - Extensive genomic studies, such as The Cancer Genome Atlas, have identified numerous genetic mutations and alterations in cancer cells that are not explained by fungal infections. - These genetic changes are often directly linked to cancer-related processes.

  4. Mechanism of action: - While some fungi can produce carcinogenic compounds, there's no clear mechanism by which fungi could consistently cause the specific genetic alterations observed in various types of cancer.

  5. Immunocompromised patients: - Patients with compromised immune systems are highly susceptible to fungal infections. If fungi were the primary cause of cancer, we would expect to see much higher cancer rates in these populations, which is not the case.

  6. Treatment efficacy: - Cancer treatments targeting cellular mechanisms and genetic alterations have shown significant efficacy, which would be unlikely if fungi were the primary cause.

  7. Experimental evidence: - Laboratory studies inducing cancer in animal models through genetic alterations or carcinogen exposure don't require fungal involvement.

  8. Tissue culture studies: - Cancer cells can be grown and studied in sterile laboratory conditions without any fungal presence, demonstrating that fungi are not necessary for cancer cell survival or proliferation.

  9. Hereditary cancers: - The existence of hereditary cancer syndromes, where specific genetic mutations dramatically increase cancer risk, is difficult to explain with a fungal infection hypothesis.

  10. Cellular and molecular biology: - Our understanding of cancer at the cellular and molecular level, including oncogene activation and tumor suppressor inactivation, doesn't require fungal involvement to explain cancer development.

  11. Inconsistency across cancer types: - Different cancers have distinct molecular profiles and risk factors. A single cause (fungi) is unlikely to explain this diversity.

  12. Successful prevention strategies: - Many cancer prevention strategies (e.g., smoking cessation, sun protection) are effective without addressing fungal infections.

  13. Lack of fungal signatures: - Sophisticated genomic analyses of tumors have not revealed consistent fungal genetic material or signatures across cancer types.

  14. Evolutionary perspective: - Cancer is observed across many animal species, including those with very different susceptibilities to fungal infections than humans.

  15. Clinical observations: - Clinicians and pathologists routinely examine cancer tissues and rarely report finding evidence of widespread fungal involvement.

While it's true that some fungi can produce carcinogenic compounds and that certain fungal infections (like chronic candidiasis) have been associated with slightly increased risk of specific cancers, the evidence overwhelmingly suggests that fungi are not the primary cause of most cancers. The scientific consensus supports a multifactorial model of cancer causation, involving genetic, environmental, and lifestyle factors, with somatic mutations playing a central role in most cases.

It's important to approach such claims critically and rely on well-established scientific evidence and consensus when considering cancer causes and treatments.

Most of Claude's points seem weak, often assuming a rather controversial belief that fungi are reliably detected when they're present. The point that looks strongest to me is the one about Immunocompromised patients.

me: What's the best source of evidence for cancer rates in immunocompromised patients?

Claude:

To find the best evidence for cancer rates in immunocompromised patients, we should look at large-scale epidemiological studies, systematic reviews, and meta-analyses. Some of the most reliable sources include:

  1. HIV/AIDS patient cohorts: The HIV/AIDS Cancer Match Study, conducted by the National Cancer Institute, is one of the most comprehensive sources. It links HIV/AIDS and cancer registry data in the United States.

Key resource: Engels, E. A., et al. (2008). Trends in cancer risk among people with AIDS in the United States 1980--2002. AIDS, 22(16), 2101-2108.

  1. Transplant recipient studies: The Transplant Cancer Match Study, also by the National Cancer Institute, is an authoritative source for cancer incidence in organ transplant recipients.

Key resource: Engels, E. A., et al. (2011). Spectrum of cancer risk among US solid organ transplant recipients. JAMA, 306(17), 1891-1901.

  1. Systematic reviews and meta-analyses: These provide comprehensive overviews of multiple studies.

Example: Grulich, A. E., et al. (2007). Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. The Lancet, 370(9581), 59-67.

  1. Large national databases: Countries with comprehensive health registries, like the Nordic countries, often provide valuable data.

Example: Vajdic, C. M., & van Leeuwen, M. T. (2009). Cancer incidence and risk factors after solid organ transplantation. International Journal of Cancer, 125(8), 1747-1754.

  1. Collaborative international studies: The International Immunocompromised Host Society (ICHS) often publishes comprehensive data.

  2. Specific immunodeficiency disorder studies: For rare immunodeficiency disorders, studies like the USIDNET (United States Immunodeficiency Network) can be valuable.

  3. World Health Organization (WHO) reports: The WHO occasionally publishes comprehensive reports on cancer in immunocompromised populations.

  4. Centers for Disease Control and Prevention (CDC): The CDC maintains databases and publishes reports on cancer incidence in HIV-infected individuals.

When evaluating these sources, consider: - Sample size - Duration of follow-up - Methodology for cancer detection and classification - Adjustment for confounding factors - Recency of the data

It's important to note that cancer rates can vary depending on the specific cause and nature of immunosuppression, so looking at multiple sources covering different immunocompromised populations can provide a more comprehensive picture.

me: What does the Somatic Mutation Theory of cancer predict about the kinds of mutations seen in the DNA of cancer cells? What kind of evidence concerning those mutations would falsify the theory?

Claude:

The Somatic Mutation Theory (SMT) of cancer makes several predictions about the kinds of mutations seen in the DNA of cancer cells. Here are the key predictions and the types of evidence that could potentially falsify the theory:

Predictions of the Somatic Mutation Theory:

  1. Accumulation of mutations: SMT predicts that cancer cells will have accumulated multiple mutations over time.

  2. Driver mutations: Some mutations (called driver mutations) will be causally implicated in cancer development, affecting genes that control cell growth, division, or death.

  3. Passenger mutations: Other mutations (called passenger mutations) will be present but not directly contributing to cancer development.

  4. Clonal expansion: Cells with advantageous mutations will undergo clonal expansion, leading to a population of cancer cells with shared mutations.

  5. Heterogeneity: Different areas of a tumor may have different sets of mutations due to ongoing mutation and selection processes.

  6. Specific gene types: Mutations will often affect proto-oncogenes (promoting cell growth) and tumor suppressor genes (inhibiting cell growth).

  7. Functional changes: Mutations will lead to functional changes in proteins that drive cancer-related processes (e.g., increased proliferation, evading apoptosis).

Evidence that could potentially falsify the theory:

  1. Lack of mutations: If cancer cells consistently showed no increase in mutations compared to normal cells, this would challenge SMT.

  2. Random distribution: If mutations in cancer cells were completely random and showed no enrichment in cancer-related genes, this would be contrary to SMT predictions.

  3. Reversibility without genetic changes: If advanced cancers could be consistently and permanently reversed to normal cells without altering their genetic material, this would challenge SMT.

  4. Lack of clonality: If cancer cells within a tumor showed no evidence of clonal relationships, this would be inconsistent with SMT.

  5. Identical mutations across cancer types: If all cancers, regardless of tissue origin or type, always had the exact same set of mutations, this would be difficult to explain with SMT.

  6. Non-genetic transmission: If cancer could be reliably transmitted between individuals or cells without any transfer of genetic material or induction of new mutations, this would challenge SMT.

  7. Perfect correlation with environmental factors: If cancer incidence was perfectly explained by environmental factors alone, with no role for random mutations or genetic susceptibility, this would be inconsistent with SMT.

  8. Lack of genomic instability: If cancer cells showed no signs of genomic instability or increased mutation rates compared to normal cells, this would be contrary to many versions of SMT.

  9. Mutations without consequences: If the identified mutations in cancer cells could be shown to have no functional consequences at all, this would challenge a key aspect of SMT.

It's important to note that while these findings would challenge SMT, they would need to be consistently replicated and thoroughly verified before the theory would be considered falsified. Many of these potential falsifying observations have not been seen; instead, the accumulating evidence has generally supported the main tenets of the Somatic Mutation Theory, though it has also led to refinements and expansions of the theory over time.

me: What does the Cancer Genome Atlas say about whether mutations in cancer cells tend to be in cancer-related genes?

Claude:

The Cancer Genome Atlas (TCGA) has provided extensive data on the genomic characteristics of various cancer types, offering significant insights into the patterns of mutations in cancer cells. Regarding your specific question about whether mutations in cancer cells tend to be in cancer-related genes, TCGA data strongly supports this notion. Here's a summary of key findings:

  1. Enrichment in cancer-related genes: TCGA data shows that mutations in cancer cells are indeed enriched in cancer-related genes. These include:
  • Oncogenes (e.g., KRAS, BRAF) - Tumor suppressor genes (e.g., TP53, PTEN) - DNA repair genes (e.g., BRCA1, BRCA2) - Cell cycle regulators (e.g., RB1, CDKN2A)
  1. Recurrent mutations: Certain genes are found to be recurrently mutated across multiple cancer types, suggesting their importance in cancer development. For example, TP53 is mutated in a high percentage of various cancers.

  2. Cancer-type specific patterns: While some genes are commonly mutated across cancer types, TCGA has also revealed cancer-type specific mutation patterns. For instance: - BRAF mutations are common in melanoma

  • APC mutations are frequent in colorectal cancer - EGFR mutations are often seen in certain lung cancers
  1. Pathway-level alterations: TCGA data shows that even when specific genes are not mutated, the pathways they belong to are often altered. This supports the idea that cancer-related processes are being targeted by mutations.

  2. Driver vs. passenger mutations: TCGA analyses have helped distinguish between driver mutations (in cancer-related genes) and passenger mutations. Driver mutations are less common but more impactful, often occurring in cancer-related genes.

  3. Mutational signatures: TCGA has revealed mutational signatures that are associated with specific cancer types or carcinogenic exposures, many of which affect cancer-related genes more frequently.

  4. Fusion genes: TCGA has identified numerous fusion genes in various cancers, often involving known cancer-related genes, further supporting the concentration of impactful mutations in cancer-relevant genomic regions.

  5. Copy number alterations: Beyond point mutations, TCGA data shows that copy number alterations (amplifications and deletions) also frequently affect cancer-related genes.

  6. Epigenetic alterations: While not mutations per se, TCGA has shown that epigenetic changes (like DNA methylation) often affect the expression of cancer-related genes.

  7. Mutual exclusivity: TCGA data has revealed patterns of mutual exclusivity among mutations in certain cancer-related genes, suggesting that altering one component of a pathway is often sufficient for cancer development.

It's important to note that while TCGA data strongly supports the concentration of mutations in cancer-related genes, it also reveals the complexity of cancer genomics:

  • Not all mutations in cancer cells are in known cancer-related genes. - The functional impact of many mutations is still not fully understood. - There's significant heterogeneity both within and between cancer types. - Some cancers show a high mutational burden across the genome, while others have fewer, more specific alterations.

In conclusion, TCGA data provides robust evidence that mutations in cancer cells tend to be enriched in cancer-related genes, supporting key aspects of the Somatic Mutation Theory of cancer. However, it also highlights the complexity of cancer genomics and the need for continued research to fully understand the role of various genetic alterations in cancer development and progression.

me: I've seen reports (via Mark Lintern) that a number of cancers involve no mutations. How do supporters of the Somatic Mutation Theory respond to such claims?

Claude:

The claim that some cancers involve no mutations is indeed a challenge to the Somatic Mutation Theory (SMT) of cancer. This topic has been a subject of debate in the cancer research community. Here's how supporters of SMT typically respond to such claims:

  1. Questioning the methodology: - SMT supporters often argue that the studies claiming "mutation-free" cancers may have limitations in their detection methods. - They suggest that more sensitive techniques or broader genomic analyses might reveal mutations that were initially missed.

  2. Epigenetic alterations: - Some SMT proponents argue that while there might not be detectable DNA sequence mutations, epigenetic changes (which can alter gene expression without changing the DNA sequence) could be present. - They consider epigenetic alterations as an extension of the mutation concept, still fitting within a broader interpretation of SMT.

  3. Inherited genetic factors: - In some cases, cancer might develop due to inherited genetic factors rather than new somatic mutations. SMT supporters argue this still fits within the genetic basis of cancer.

  4. Chromosomal abnormalities: - Some cancers might have large-scale chromosomal abnormalities (like aneuploidy) rather than point mutations. These are still genetic changes consistent with SMT.

  5. Viral oncogenesis: - In cancers caused by viruses, the viral genes might drive cancer development without new mutations in the host genome. SMT supporters argue this still involves genetic alterations, albeit from an external source.

  6. Rare exceptions: - SMT proponents often argue that even if some cancers truly lack mutations, these are likely rare exceptions that don't invalidate the theory for the vast majority of cancers.

  7. Limitations of current knowledge: - They might argue that our current understanding of cancer-related genes is incomplete, and mutations in yet-unknown cancer-related genes might be present.

  8. Challenging the "mutation-free" claim: - Some supporters question whether truly "mutation-free" cancers exist, suggesting that more comprehensive analyses would likely reveal some level of genetic alteration.

  9. Fusion genes and other structural variations: - Some genetic alterations, like gene fusions, might not be detected by methods looking for point mutations but still represent genetic changes consistent with SMT.

  10. Mosaicism and low-frequency mutations: - They argue that some mutations might be present in only a small subset of cells or at very low frequencies, making them difficult to detect with standard methods.

  11. Expanding the definition of "mutation": - Some researchers propose broadening the definition of mutations to include other types of genetic and epigenetic alterations, thus maintaining the core of SMT while accommodating new findings.

  12. Integrating with other theories: - Many SMT supporters advocate for an integrated view of cancer development, incorporating aspects of other theories (like the metabolic theory or tissue organization field theory) while maintaining the central role of genetic alterations.

It's worth noting that the cancer research community continues to debate and refine theories based on new evidence. While SMT remains a dominant paradigm, many researchers acknowledge that it may not fully explain all aspects of cancer development and progression. The field is moving towards more nuanced and integrated models of cancer biology that can account for the complex and diverse nature of the disease.

Replies from: mishka
comment by mishka · 2024-07-24T03:32:36.119Z · LW(p) · GW(p)

Thanks for the book review!

Effectiveness of current treatments: Many existing cancer treatments that do not specifically target fungal infections have shown efficacy in treating various types of cancer, which may contradict the theory that fungi are the primary cause [1].

That stands out as strange. The "effectiveness" of current cancer treatments is what led me to search for what is wrong with cancer research.

But don't we have a bunch of cancer subtypes where we have had drastic treatment improvements in recent years?

Those improvements seem to be arguments against "single cause" approaches (although a particular "single cause" could still dominate a good chunk of the cancer types and could be an important factor almost everywhere).

Replies from: Jesper Lindholm
comment by Jesper Lindholm · 2024-07-24T13:05:38.544Z · LW(p) · GW(p)

Why on Earth are you downvoted? Some new norm rule about neural network compilers that people blindly follow?

As a molecular and cellular biologist trained in cancer studies, of the original arguments listed by AI against the theory, no. 6,7,8,11,12 all depend on directly contradicting the theories, not allowing a combination of them, and are thus weak counter points. But all other points discredits the theory on its own merits.