mutation etiketine sahip kayıtlar gösteriliyor. Tüm kayıtları göster
mutation etiketine sahip kayıtlar gösteriliyor. Tüm kayıtları göster

The (bad) luck of the draw; more evidence

A while back, Vogelstein and Tomasetti (V-T) published a paper in Science in which it was argued that most cancers cannot be attributed to known environmental factors, but instead were due simply to the errors in DNA replication that occur throughout life when cells divide.  See our earlier 2-part series on this.

Essentially the argument is that knowledge of the approximate number of at-risk cell divisions per unit of age could account for the age-related pattern of increase in cancers of different organs, if one ignored some obviously environmental causes like smoking.  Cigarette smoke is a mutagen and if cancer is a mutagenic disease, as it certainly largely is, then that will account for the dose-related pattern of lung and oral cancers.

This got enraged responses from environmental epidemiologists whose careers are vested in the idea that if people would avoid carcinogens they'd reduce their cancer risk.  Of course, this is partly just the environmental epidemiologists' natural reaction to their ox being gored--threats to their grant largesse and so on.  But it is also true that environmental factors of various kinds, in addition to smoking, have been associated with cancer; some dietary components, viruses, sunlight, even diagnostic x-rays if done early and often enough, and other factors.

Most associated risks from agents like these are small, compared to smoking, but not zero and an at least legitimate objection to V-T's paper might be that the suggestion that environmental pollution, dietary excess, and so on don't matter when it comes to cancer is wrong.  I think V-T are saying no such thing.  Clearly some environmental exposures are mutagens and it would be a really hard-core reactionary to deny that mutations are unrelated to cancer.  Other external or lifestyle agents are mitogens; they stimulate cell division, and it would be silly not to think they could have a role in cancer.  If and when they do, it is not by causing mutations per se.  Instead mitogenic exposures in themselves just stimulate cell division, which is dangerous if the cell is already transformed into a cancer cell.  But it is also a way to increase cancer by just what V-T stress: the natural occurrence of mutations when cells divide.

There are a few who argue that cancer is due to transposable elements moving around and/or inserting into the genome where they can cause cells to misbehave, or other perhaps unknown factors such as of tissue organization, which can lead cells to 'misbehave', rather than mutations.

These alternatives are, currently, a rather minor cause of cancer.  In response to their critics, V-T have just published a new multi-national analysis that they suggest supports their theory.  They attempted to correct for the number of at-risk cells and so on, and found a convincing pattern that supports the intrinsic-mutation viewpoint.  They did this to rebut their critics.

This is at least in part an unnecessary food-fight.  When cells divide, DNA replication errors occur.  This seems well-documented (indeed, Vogelstein did some work years ago that showed evidence for somatic mutation--that is, DNA changes that are not inherited--and genomes of cancer cells compared to normal cells of the same individual.  Indeed, for decades this has been known in various levels of detail.  Of course, showing that this is causal rather than coincidental is a separate problem, because the fact of mutations occurring during cell division doesn't necessarily mean that the mutations are causal. However, for several cancers the repeated involvement of specific genes, and the demonstration of mutations in the same gene or genes in many different individuals, or of the same effect in experimental mice and so on, is persuasive evidence that mutational change is important in cancer.

The specifics of that importance are in a sense somewhat separate from the assertion that environmental epidemiologists are complaining about.  Unfortunately, to a great extent this is a silly debate. In essence, besides professional pride and careerism, the debate should not be about whether mutations are involved in cancer causation but whether specific environmental sources of mutation are identifiable and individually strong enough, as x-rays and tobacco smoke are, to be identified and avoided.  Smoking targets particular cells in the oral cavity and lungs.  But exposures that are more generic, but individually rare or not associated with a specific item like smoking, and can't be avoided, might raise the rate of somatic mutation generally.  Just having a body temperature may be one such factor, for example.

I would say that we are inevitably exposed to chemicals and so on that will potentially damage cells, mutation being one such effect.  V-T are substantially correct, from what the data look like, in saying that (in our words) namable, specific, and avoidable environmental mutations are not the major systematic, organ-targeting cause of cancer.  Vague and/or generic exposure to mutagens will lead to mutations more or less randomly among our cells (maybe, depending on the agent, differently depending on how deep in our bodies the cells are relative to the outside world or other means of exposure).  The more at-risk cells, the longer they're at risk, and so on, the greater the chance that some cell will experience a transforming set of changes.

Most of us probably inherit mutations in some of these genes from conception, and have to await other events to occur (whether these are mutational or of another nature as mentioned above).  The age patterns of cancers seem very convincingly to show that.  The real key factor here is the degree to which specific, identifiable, avoidable mutational agents can be identified.  It seems silly or, perhaps as likely, mere professional jealousy, to resist that idea.

These statements apply even if cancers are not all, or not entirely, due to mutational effects.  And, remember, not all of the mutations required to transform a cell need be of somatic origin.  Since cancer is mostly, and obviously, a multi-factor disease genetically (not a single mutation as a rule), we should not have our hackles raised if we find what seems obvious, that mutations are part of cell division, part of life.

There are curious things about cancer, such as our large body size but delayed onset ages relative to the occurrence of cancer in smaller, and younger animals like mice.  And different animals of different lifespans and body sizes, even different rodents, have different lifetime cancer risks (some may be the result of details of their inbreeding history or of inbreeding itself).  Mouse cancer rates increase with age and hence the number of at-risk cell divisions, but the overall risk at very young ages despite many fewer cell divisions (yet similar genome sizes) shows that even the spontaneous mutation idea of V-T has problems.  After all, elephants are huge and live very long lives; why don't they get cancer much earlier?

Overall, if if correct, V-T's view should not give too much comfort to our 'Precision' genomic medicine sloganeers, another aspect of budget protection, because the bad luck mutations are generally somatic, not germline, and hence not susceptible to Big Data epidemiology, genetic or otherwise, that depends on germ-line variation as the predictor.

Related to this are the numerous reports of changes in life expectancy among various segments of society and how they are changing based on behaviors, most recently, for example, the opiod epidemic among whites in depressed areas of the US.  Such environmental changes are not predictable specifically, not even in principle, and can't be built into genome-based Big Data, or the budget-promoting promises coming out of NIH about such 'precision'.  Even estimated lifetime cancer risks associated with mutations in clear-cut risk-affecting genes like BRCA1 mutations and breast cancer, vary greatly from population to population and study to study.  The V-T debate, and their obviously valid point, regardless of the details, is only part of the lifetime cancer risk story.

ADDENDUM 1
Just after posting this, I learned of a new story on this 'controversy' in The Atlantic.  It is really a silly debate, as noted in my original version.  It tacitly makes many different assumptions about whether this or that tinkering with our lifestyles will add to or reduce the risk of cancer and hence support the anti-V-T lobby.  If we're going to get into the nitty-gritty and typically very minor details about, for example, whether the statistical colon-cancer-protective effect of aspirin shows that V-T were wrong, then this really does smell of academic territory defense.

Why do I say that?  Because if we go down that road, we'll have to say that statins are cancer-causing, and so is exercise, and kidney transplants and who knows what else.  They cause cancer by allowing people to live longer, and accumulate more mutational damage to their cells.  And the supposedly serious opioid epidemic among Trump supporters actually is protective, because those people are dying earlier and not getting cancer!

The main point is that mutations are clearly involved in carcinogenesis, cell division life-history is clearly involved in carcinogenesis, environmental mutagens are clearly involved in carcinogenesis, and inherited mutations are clearly contributory to the additional effects of life-history events.  The silly extremism to which the objectors to V-T would take us would be to say that, obviously, if we avoided any interaction whatsoever with our environment, we'd never get cancer.  Of course, we'd all be so demented and immobilized with diverse organ-system failures that we wouldn't realize our good fortune in not getting cancer.

The story and much of the discussion on all sides is also rather naive even about the nature of cancer (and how many or of which mutations etc it takes to get cancer); but that's for another post sometime.

ADDENDUM 2
I'll add another new bit to my post, that I hadn't thought of when I wrote the original.  We have many ways to estimate mutation rates, in nature and in the laboratory.  They include parent-offspring comparison in genomewide sequencing samples, and there have been sperm-to-sperm comparisons.  I'm sure there are many other sets of data (see Michael Lynch in Trends in Genetics 2010 Aug; 26(8): 345–352.  These give a consistent picture and one can say, if one wants to, that the inherent mutation rate is due to identifiable environmental factors, but given the breadth of the data that's not much different than saying that mutations are 'in the air'.  There are even sex-specific differences.

The numerous mutation detection and repair mechanisms, built into genomes, adds to the idea that mutations are part of life, for example that they are not related to modern human lifestyles.  Of course, evolution depends on mutation, so it cannot and never has been reduced to zero--a species that couldn't change doesn't last.  Mutations occur in plants and animals and prokaryotes, in all environments and I believe, generally at rather similar species-specific rates.

If you want to argue that every mutation has an external (environmental) cause rather than an internal molecular one, that is merely saying there's no randomness in life or imperfection in molecular processes.  That is as much a philosophical as an empirical assertion (as perhaps any quantum physicist can tell you!).  The key, as  asserted in the post here, is that for the environmentalists' claim to make sense, to be a mutational cause in the meaningful sense, the force or factor must be systematic and identifiable and tissue-specific, and it must be shown how it gets to the internal tissue in question and not to other tissues on the way in, etc.

Given how difficult it has been to chase down most environmental carcinogenic factors, to which exposure is more than very rare, and that the search has been going on for a very long time, and only a few have been found that are, in themselves, clearly causal (ultraviolet radiation, Human Papilloma Virus, ionizing radiation, the ones mentioned in the post), whatever is left over must be very weak, non tissue-specific, rare, and the like.  Even radiation-induced lung cancer in uranium minors has been challenging to prove (for example, because miners also largely were smokers).

It is not much of a stretch to simply say that even if, in principle, all mutations in our body's lifetime were due to external exposures, and the relevant mutagens could be identified and shown in some convincing way to be specifically carcinogenic in specific tissues, in practice if not ultra-reality, then the aggregate exposures to such mutations are unavoidable and epistemically random with respect to tissue and gene.  That I would say is the essence of the V-T finding.

Quibbling about that aspect of carcinogenesis is for those who have already determined how many angels dance on the head of a pin.

Darwin the Newtonian. Part II. Is life really 'Newtonian'?

In yesterday's post I suggested that Darwin had a Newtonian view of the world, that is, he repeatedly and clearly described the organisms and diversity of life as the product of evolution, due to natural selection viewed as a force, which in an implicit way he likened to gravity.  At the same time, he knew that there was widespread evidence of various kinds for long-term evolutionary stasis, which a prominent geologist has recently called  "Darwin's null hypothesis of evolution," the idea that evolution does not occur if the environment stays the same.

That suggests that a changing environment leads to a changing mix of organisms that live in the environment, including of their genotypes.  It makes evolutionary sense, of course, because environments screen organisms for 'fitness'.  However, its negative--no change in the environment implies no evolution-- doesn't make sense and badly misrepresents what is widely assumed that we know about evolution. Even if we define evolution, as often done in textbooks, as 'change in gene frequencies' such change clearly occurs even in stable environments.  Mutations always arise, and selectively neutral variants, that is, that don't affect the fitness of their bearers, change in frequency by chance alone, not by natural selection, which means that at the genomic level evolution still occurs. It's curious that not only can organisms stay very similar in what seem like static environments, but also can be similar even in changing environments.

The idea of dual environmental-genetic stasis is an inference made from species that seem to stay similar for long time periods in environments that also appear similar--but how similar are they really?

Indeed, there are several problems with the widely if often implicitly assumed 'null hypothesis':

  1.  It is a very narrow assumption of the meaning of 'evolution', implicitly implying that it refers only to functionally important traits or their underlying genotypes. As we will see, there are ways for genetic change (and even trait change) to occur even in static environments, so that an unchanging environment doesn't imply no biological change.
  2.  It implies that 'the environment' actually stays the same, although 'environment' is hard to define.
  3.  It implies a tight essentially one-to-one fit between genotype and adaptive traits, so that in unchanging environments there will not be any functional genomic change.

All of these assumptions are wrong.  In essence, there cannot be 'the', or even 'a' null hypothesis for evolution.   Sexual reproduction, horizontal transfer, and recombination occur even without new sequence mutation.  To ignore that along with assuming a stationary environment, and adopt a null hypothesis that had anything like mathematical or Aristotelian rigor would be to reduce evolution's basis to something like this not-very-profound tautology:  Everything stays the same, if everything stays the same.

So let's look at this a little more closely
From the fossil record, we infer that some species stay the 'same' for eons, sometimes millions of years.  Then they change.  Gould and Eldridge called this 'punctuated equilibrium' and it was taken as a kind of up-dated version of Darwinism--mistakenly, because Darwin recognized it very clearly at least by the 6th edition of his Origin.  And while some aspects of animals and plants can hardly change in appearance for long time periods, close inspection shows that only some aspects of what can be preserved in fossils stays similar; other aspects typically change.  Also, speciation events occur and some descendants of an early form do change in form, even if the older species seems not to change. So we should be very careful even to suggest that environments or species really are not changing.

But mutations certainly occur and that means that even for a set of fossils that look the same, the genomes of the individuals would have varied, at least in non-functional sequence elements.  That itself is 'evolution', and it is misleading to restrict the term only to visible functional change.  But genetic drift is just the tip of the molecular evolution iceberg.  It is now very clear that there are many ways for an organism to produce what appears to be the same trait--and this is true both at the molecular and morphological levels.  That is, even a trait that 'looks' the same can be produced by different genotypes.  I wrote about this long ago in a rather simple vein, calling it phenogenetic drift, and Andreas Wagner in particular has written extensively about it, with sophisticated technical detail, in his book The Origin of Evolutionary Innovation, and this paper.  (The images are of my general paper and Wagner's book given just to break up the monotony of long text! ; he has written a more popular-level book as well called Arrival of the Fittest, which is a very good introduction to these ideas).

Recent exploration, with great detail



A modest statement of principl


Wagner explores this in many ways and among his views is that the ability of organisms to evolve innovative traits is based on the huge number of overlapping, essentially similar ways it can carry out its various functions, which allows mutations to add new function without jeopardizing the current one. Redundancy is protective against environmental changes as well as enabling new traits to arise.

This is in a sense no news at all. It was implicit in the very foundational concept of 'polygenic' control-- the determination of a trait by independent, or semi-independent of many different genes.  The way complex traits are thus constructed was clear to various biologists more than a century ago, even if the specific genes could not be identified (and the nature of a 'gene' was unknown).  A fundamental implication of the idea for our current purposes is that each individual with a given trait value (say, two people with the same height or blood pressure) can have its own underlying multi-locus genotype, which can vary among them.  Genotypes may predict phenotypes, but a phenotype does not accurately predict the underlying genotype (a deep lesson that many who promote simplistic models of causation in biomedical contexts should have learned in school).

And of course that does not even consider environmental effects, even though we know very well that for most characters of interest, normal or pathological, 'genetic' factors account only for a modest fraction of their variation. And, of course, if it's hard to identify contributing genetic variants, it's at least as difficult to identify the complex environmental contributors who make inference of phenotype from genotype so problematic. That is, neither does genotype reliably predict phenotype, nor does phenotype reliably predict genotype and the idea that they do so with 'precision' (to use todays' fashionable branding phrase) is very misleading.

In turn, these considerations imply that even if we accepted the idea of natural selection as a Newtonian deterministic force, it works at the level of the achieved trait, and can ignore (actually, is blinded to) the underlying causal genetic mechanism.  There can be extensive variation within populations in the latter, and change over time.  Just because two individuals now or in the past have a similar trait does not imply they have the same underlying genotype and hence does not imply there's been no 'evolution' even in that stable trait!

In this sense, evolution could be Newtonian, driven by force-like selection, and still not be genetically static.  But there's more.  How can there actually be stasis in a local environment?  If organisms adapt to conditions, then that in itself changes those conditions.  Even within a species, as more and more of its members take on some adaptive response to the environment, they change their own relative fitness by changing the mix of genotypes in their population, and that in turn will affect their predators and prey, their mate selection, and the various ways that the mix of resources are used in the local ecology.  If, say, the members of a species become bigger, or faster, or better at smelling prey, then the distribution of energy and species size must also change.  That is, the 'environment' cannot really remain the same.  That ecosystems are fundamentally dynamic has long been a core aspect of population ecology.

In a nutshell, it must be true that if genotypes change, that changes the local environment because my genotype is part of everybody else's 'environment'. In that sense, only if no mutations are possible can there be no 'evolution'. Even if one wants to argue that all mutations that arise are purged in order to keep the species the 'same', there will still be a dynamic mix of mutational variants over time and place.

One could even assert that an essence of Darwinism, literally interpreted, is that environments cannot be the same because the adaptation of one species affects others, even were new mutations not arising, because it affects the fitness of others. That is what his idea of the relentless struggle for existence among species meant, so stasis did cause him a bit of a problem, which he recognized in the later edition of the Origin.

I think that in essence Darwin viewed natural selection as being basically a deterministic force, like gravity, corresponding to Newton's second law of motion. And the idea of stasis corresponds to Newton's first law, of inertia. Today even many knowledgeable biologists seem to think in that way (for example, invoking drift only as a minor source of 'noise' in otherwise force-like adaptive evolution). Selective explanations are offered routinely as true, and the word 'force' routinely is used to explain how traits got here.
But there are deep problems even if we accept this view as correct.  Among other things, even if natural selection is really force-like, or if genetic drift exists as a moderating factor, then these factors should have some properties that we could test, at least in principle.  But as we'll see next time, it's not at all clear that that is the case.

If mutations can go viral, adaptationism is less annoying.

Feb. 9, 2016: I have edited the paragraph beginning with "Exciting..." to remove details of mutation rates because my initial posting was probably wrong about coding vs. non-coding mutation rates. To fix that requires much more nuance than is relevant for the point I'm making in that paragraph, not to mention much more nuance than I'm capable of grasping immediately! Cheers and thanks to Daniel and Ken in comments below and to everyone who chimed in on Twitter. 
***
I always account for virally-induced mutation when I imagine the evolution of our genome. That's because I'll never forget this quote. Who could?
“Our genome is littered with the rotting carcasses of these little viruses that have made their home in our genome for millions of years.” - David Haussler in 2008 
Or this...
"Retroviruses are the only group of viruses known to have left a fossil record, in the form of endogenous proviruses, and approximately 8% of the human genome is made up of these elements." (source and see this)
Exciting virus discoveries aside, we're constantly mutating with each new addition to the human lineage. Thanks to whole genome sequencing, the rate of new mutation between human parent and offspring is becoming better known than ever before. We each have new single nucleotide mutations in the stretches of our DNA that are known to be functional (very little of the entire genome) and that are not (the majority of the genome). These are variants not present in our parents’ codes (for example, we might have a ‘T’ where there is a ‘A’ in our mother’s code). And there are also deletions and duplications of strings of letters in the code, sometimes very long ones. Estimates vary on parent-offspring mutation rate and that's because there are different sorts of mutations and individuals vary, even as they age, as to how many mutations they pass along, for example. Still, without any hard numbers (which I've left out purposefully to avoid the mutation rate debate), knowing that there is constant mutation is helpful for imagining how evolution works. And it also helps us understand how mutations even in coding regions aren't necessarily good nor bad. Most mutations in our genome are just riding along in our mutation-tolerant codeswhere they will begin and where they will go no one knows!

And it's with that appreciation for constant, unpredictable, but tolerated mutationof evolution's momentum, of a lineage's perpetual change, selection or noton top of a general understanding of population genetics that just makes adaptation seem astounding. It makes it difficult to believe that adaptation is as common as the myriad adaptive hypotheses for myriad traits suggest.

That's because this new raw material for adaptation, this perpetual mutation, really is only a tiny fragment of everything that can be passed on. But, what's more, each of those itty bitty changes could be stopped in its tracks before going anywhere.

The good, the bad, and the neutral, they all need luck to pass them onto the next generation. That's right. Even the good mutations have it rough. Even the winners can be losers! Here are the ways a mutation can live or die in you or me:

The Brief or Wondrous Life of Mutations, Wow.

This view of mutation fits into that slow and stately process that Darwin described, despite his imagination chugging away before he had much understanding of genetics.

Of course, bottlenecks or being part small populations would certainly help our rogue underdogs proliferate, and swiftlier so, in future generations.

Still, trying to imagine how any of my mutations, including any that might be adaptive, could become fixed in a population is enough to make me throw Origin of Species across the room.

By "adaptive," I'm talking about "better" or "advantageous" traits and their inherited basis ... that ever-popular take on the classic Darwinian idea of natural selection and competition.

For many with a view of mutation like I spelled out above, it's much easier to conceptualize adaptation as the result of negative selection, stabilizing selection, and tolerant or weak selection than it is to accept stories of full-blown positive selection, which is what "Darwinian" usually describes (whether or not that was Darwin's intention). One little error in one dude's DNA plus deep time goes all the way to fixed in the entire species because those who were lucky enough to inherit the error passed it on more frequently, because they had that error, than anyone passed on the old version of that code? I guess what I'm saying is, it's not entirely satisfying.

But what if a mutation could be less pitiful, less lonely, less vulnerable to immediate extinction? Instead, what if a mutation could arise in many people simultaneously? What if a mutation didn't have to start out as 1/10,000? What if it began as 1,000/10,000?

That would certainly up its chances of increasing in frequency over time, and quickly, relative to the rogue underdog way that I hashed out in the figure above. And that means that if there was a mutation that did increase survival and reproduction relative to the status quo, it would have a better chance to actually take over as an adaptation. This would be aided, especially, if there was non-random mating, like assortative mating, creating a population rife with this beneficial mutation in the geologic blink of an eye.

But how could such a widespread mutation arise? This sounds so heartless to put it like this, but thanks to the Zika virus, it seems to me that viruses could do the trick.

Electron micrograph of Zika virus. (wikipedia)
I'd been trapped in thinking that viruses cause unique mutations in our genomes the way that copy errors do. But why should they? If they infect me and you, they could leave the same signatures in our genomes. And the number of infected/mutated could increase if the virus is transmitted via multiple species (e.g. mosquito and human, like Zika). If scientists figure out that the rampant microcephaly associated with the Zika virus is congenital, wouldn't this be an example* of the kind of large-scale mutation that I'm talking about? 

*albeit a horrifying one, and unlikely to get passed on because of its effects, so it's not adaptive whatsoever.

If viral mutations get into our gametes or into the stem cells of our developing embryos, then we've got germ-line mutation and we could have the same germ-line mutation in the many many genomes of those infected with the virus. As long as we survive the virus, and we reproduce, then we'll have these mutant babies who don't just have their own unique mutations, but they also have these new but shared mutations and the shared new phenotypes associated with them, simultaneously.

Why not? Well, not if there are no viruses that ever work like this.

We need some examples. The mammalian placenta, and its subsequent diversity, is said to have begun virally, but I can't find any writing that assumes anything other than a little snowflake mutation-that-could.

Anything else? Any traits that "make us human"? Any traits that are pegged as convergences but could be due to the mutual hosting of the same virus exacting the same kind of mutation with the same phenotypic result in separate lineages?

I've always had a soft spot for underdogs. And I've always given the one-off mutation concept the benefit of the doubt because I know that my imagination struggles to appreciate deep time. What choice do you have when you think evolutionarily? However, just the possibility that viruses can mutate us at this larger scale, even though I know of no examples, is already bringing me a little bit of hope and peace, and also some much needed patience for adaptationism.

***
Update: I just saw this published today, asking whether microcephaly and other virus-induced birth defects are congenital. Answer = no one knows yet: http://www.nytimes.com/2016/02/09/science/zika-virus-microcephaly-birth-defects-rubella-cytomegalovirus.html?partner=IFTTT&_r=1

Food-Fight Alert!! Is cancer bad luck or environment? Part I: the basic issues

Not long ago Vogelstein and Tomasetti stirred the pot by suggesting that most cancer was due to the bad luck of inherent mutational events in cell duplication, rather than to exposure to environmental agents.  We wrote a pair of posts on this at the time. Of course, we know that many environmental factors, such as ionizing radiation and smoking, contribute causally to cancer because (1) they are known mutagens, and (2) there are dose or exposure relationships with subsequent cancer incidence. However, most known or suspected environmental exposures do not change cancer risk very much or if they do it is difficult to estimate or even prove the effect.  For the purposes of this post we'll simplify things and assume that what transforms normal cells into cancer cells is genetic mutations; though causation isn't always so straightforward, that won't change our basic storyline here.

Vogelstein and Tomasetti upset the environmental epidemiologists' apple cart by using some statistical analysis of cancer risks related, essentially, to the number of cells at risk, their normal time of renewal by cell division, and age (time as correlated with number of cell divisions).  Again simplifying, the number of at-risk actively dividing cells is correlated with the risk of cancer, as a function of age (reflecting time for cell mutational events), and with a couple of major exceptions like smoking, this result did not require including data on exposure to known mutagens.  V and T suggested that the inherently imperfect process of DNA replication in cell division could, in itself, account for the age- and tissue-specific patterns of cancer.  V and T estimated that except for the clear cases like smoking, a large fraction of cancers were not 'environmental' in the primary causal sense, but were just due, as they said, to bad luck: the wrong set of mutations occurring in some line of body cells due to inherent mutation when DNA is copied before cell division, and not detected or corrected by the cell.  Their point was that, excepting some clear-cut environmental risks such as ionizing and ultraviolet radiation and smoking, cancer can't be prevented by life-style changes, because its occurrence is largely due to the inherent mutations arising from imperfect DNA replication.

Boy, did this cause a stink among environmental epidemiologists!  Now one we think undeniable factor in this food fight is that environmental epidemologists and the schools of public health that support them (or, more accurately, that the epidemiologists support with their grants) would be put out of business if their very long, very large, and very expensive studies of environmental risk (and the huge percent of additional overhead that pays the schools' members meal-tickets) were undercut--and not funded and the money went elsewhere.  In a sense of lost pride, which is always a factor in science because it's run by humans, all that epidemiological work would go to waste, to the chagrin of many, if it was based on misunderstanding the basic nature of the mutagenic and hence carcinogenic processes.

So naturally the V and T explanation has been heavily criticized from within the industry.  But they will also raise the point, and it's a valid one, that we clearly are exposed to many different agents and chemicals that are the result of our culture and not inevitable and are known to cause mutations in cell culture, and these certainly must contribute to cancer risk.  The environmentalists naturally want the bulk of causation to be due to such lifestyle factors because (1) they do exist, and (2) they are preventable at least in principle.  They don't in principle object to the reality that inherent mutations do arise and can contribute to cancer risk, but they assert that most cancer is due to bad behavior rather than bad luck and hence we should concentrate on changing our behavior.

Now in response, a paper in Nature ("Substantial contribution of extrinsic risk factors to cancer development," Wu et al.) provides a statistical analysis of cancer data that is a rebuttal to V and T's assertions.  The authors present various arguments to rebut V and T's assertion that most cancer can be attributed to inherent mutation, and argue instead that external factors account for 70 to 90% of risk.  So there!

In fact, these are a variety of technical arguments, and you can judge which seem more persuasive (many blog and other commentaries are also available as this question hits home to important issues--including vested interests).  But nobody can credibly deny that both environment and inherent DNA replication errors are involved.  DNA replication is demonstrably subject to uncorrected mutational change, and that (for example) is what has largely driven evolution--unless epidemiologists want to argue that for all species in history, lifestyle factors were the major mutagens, which is plausible but very hard to prove in any credible sense.  

At the same time, environmental agents do include mutational effects of various sorts and higher doses generally mean more mutations and higher risk.  So the gist of the legitimate argument (besides professional pride or territoriality and preservation of public health's mega-studies) is really the relative importance of environment vs inherent processes.  The territoriality component of this is reminiscent of the angry assertion among geneticists, about 30 years ago, that environmental epidemiologists and their very expensive studies were soaking up all the money so geneticists couldn't get much of it.  That is one reason geneticists were so delighted when cheap genome sequencing and genetic epidemiological studies (like GWAS) came along, promising to solve problems that environmental epidemiology wasn't answering--to show that it's all in the genes (and so that's where the funding should go).  

But back to basic biology 
Cells in each of our tissues have their own life history.  Many or most tissues are comprised of specialized stem cells that divide and one of the daughter cells differentiates into a mature cell of that tissue type.  This is how, for example, the actively secreting or absorbing cells in the gut are produced and replaced during life.  Various circumstances inherent and environmentally derived can affect the rate of such cell division. Stimulating division is not the same as being a direct mutagen, but there is a confounding because more cell division means more inherent mutational accumulation.  That is, an environmental component can increase risk without being a mutagen and the mutation is due to inherent DNA replication error.  Cell division rates among our different tissues vary quite a lot, as some tissues are continually renewing during life, others less so, some renew under specific circumstances (e.g., pregnancy or hormonal cycles), and so on.

As we age, cell divisions slow down, also in patterned ways.  So mutations will accumulate more slowly and they may be less likely to cause an affected cell to divide rapidly.  After menopause, breast cells slow or stop dividing.  Other cells, as in the gut or other organs, may still divide, but less often.  Since mutation, whether caused by bad luck or by mutagenic agents, affects cells when they divide and copy their DNA, mutation rates and hence cancer rates often slow with advancing age.  So the rate of cancer incidence is age-specific as well as related to the size of organs and lifestyle stimulates to growth or mutation.  These are at least a general characteristics of cancer epidemiology.

It would be very surprising if there were no age-related aspect to cancer (as there is with most degenerative disease).  The absolute risk might diminish with lower exposure to environmental mutagens or mitogens, but the replicability and international consistency of basic patterns suggests inherent cytological etiology.  It does not, of course, in any sense rule out environmental factors working in concert with normal tissue activity, so that as noted above it's not easy to isolate environment from inherent causes.

Wu et al.'s analysis makes many assumptions, the data (on exposures and cell-counts) are suspect in many ways, and it is difficult to accept that any particular analysis is definitive.  And in any case, since both types of causation are clearly at work, where is the importance of the particular percentages of risk due to each?  Clearly strong avoidable risks should be avoided, but clearly we should not chase down every miniscule risk or complex unavoidable lifestyle aspect, when we know inherent mutations arise and we have a lot of important diseases to try to understand better, not just cancer.

Given this, and without discussing the fine points of the statistical arguments, the obvious bottom line that both camps agree on is that both inherent and environmental mutagenic factors contribute to cancer risk. However, having summarized these points generally, we would like to make a more subtle point about this, that in a sense shows how senseless the argument is (except for the money that's at stake). As we've noted before, if you take into account the age-dependency of risk of diseases of this sort, and the competing causes that are there to take us away, both sides in this food fight come away with egg on their face.  We'll explain what we mean, tomorrow.

Rare Disease Day and the promises of personalized medicine

O ur daughter Ellen wrote the post that I republish below 3 years ago, and we've reposted it in commemoration of Rare Disease Day, Febru...