Cancer and Evolutionary Theory


(Peaceful Science) #1

So I am please to announce my first Nature Genetics paper:

The real reason I am posting here is to reopen the conversation about the usefulness of evolutionary theory. It turns out that evolutionary theory is indispensable to understanding cancer. The link I offered above leverages evolution for just this purpose. Though I am hardly unique. See for example this article aimed a wide audience…

http://phenomena.nationalgeographic.com/2012/01/12/inside-darwins-tumor/

And several article from the literature…


From this body of work, we can see the evolution of new functions (new information!), neutral theory, and the effectiveness of obtuse metrics like Ks/Ka ratios. It would hard to imagine rejecting evolution of species without somehow forgetting everything we have learned about the evolution of cancer.

I’m happy to answers questions about this work. =)


(Phil) #2

thank you for sharing. Interesting and important work. Ultimately, cancer treatment will be more targeted and specific than today, with less collateral damage. We are moving that way with research such as this.


(Benjamin Kirk) #3

Congrats, Joshua!


(Jon) #4

This is fantastic. Evolution vindicated yet again with actual real world experimentation and testing. I wonder what the ID explanation for cancer is? Do they think it was “intelligently designed”?


(Peaceful Science) #5

I think they would correctly point out that cancer is not a new species.

The bigger question is this: if (1) evolutionary genetic tools correctly infer the progress and history of cancer, (2) cancer regularly innovates with proteins of novel function, (3) regularly exhibits convergence at a molecular level, and (4) all the mathematical of machinery of neutral theory works so well, THEN what magically prevents all these things from being true at the species level?

This all cannot be true for cancer, but false for evolution. That is the real inconvenience here.


(Jon) #6

lol! And contains “no new information”! Which these days has been watered down to “no new COMPLEX information”.

Indeed, indeed. If they were just honest about ID and called it theology, it would be easier to take them seriously.


Criticisms vs. Attacks: Where's the line?
(Peaceful Science) #7

Put another way, if many ID arguments in molecular biology were true, then cancer as we know it would be mathematically impossible, or regularly require the direct intervention of God to initiate and be sustained. I’m not sure which option is harder to believe.

To be clear, this does not in itself prove evolution is true. Rather, it casts serious doubt on the ID arguments from molecular biology (vis-a-vis Doug Axe and Kirk Durston, etc.).


(Jon) #8

A veritable Scylla and Charybdis. I remember when the “flagellum motor” was the hottest ID argument on the block. I was intrigued and impressed. I thought ID might actually be going somewhere. But having been highly sensitized to “god of the gaps” arguments as a result of combating YEC and moving gradually out of OEC, I just couldn’t see a solid evidence based argument. And the more the surface was scratched, the faster the argument broke down. It was very disappointing actually.


(Peaceful Science) #9

Right now the most exciting possibility is immunotherapy. This could be the game changer.


#10

HeLa cells are pretty robust on their own. There are numerous single-celled organisms with narrower environmental niches. Now, if HeLa cells had a more developed recombination mechanism…


#11

Yes… for a few more cancers. I doubt any single-agent approach is going to be the answer in most cases. The Achilles heel of targeted therapeutics is that cancers develop as populations carrying diverse mutations. You can target the most prevalent or the most responsive sub-populations but you’ll ultimately need additional therapies to eliminate the remaining, resistant cells. The multi-drug combination model used successfully against HIV is progressing in cancer research but there are many, difficult obstacles associated with testing potential combinations in clinical situations.


(Peaceful Science) #12

Immunotherapy is more powerful than this because it is a new paradigm for treating cancers, that adapts to their changing mutations.

The current therapy that is showing broad spectrum efficacy is “checkpoint inhibitors.” http://blog.dana-farber.org/insight/2015/09/what-is-a-checkpoint-inhibitor/ Unlike most cancer drugs, these work on the healthy immune cells, not on the cancer itself, so this reduces the ability to escape its effect.

After that is promising results from personalized cancer vaccines (based on neoantigens). http://www.sciencemag.org/news/2015/04/personalized-cancer-vaccines-may-fight-tumors Here, again, the target is healthy immune cells, that have the ability to adapt as the cancer adapts to automatically learn the new antigens that arise.

Of course, there is reason to hope these approaches will work synergistically together, and with other approaches like chemotherapy and radiation therapy. It is important to recognize that this is a fundamentally new approach to treating cancer, and it is seeing real efficacy in patients already.


#13

Everything extra can help and that therapy will certainly be useful. It’s absolutely important research. I caution that most new therapies have been heralded as game changing. And they are for a particular subset of cancers or patients.

I think the next major innovation will come from the ability to devise patient-tailored, combination therapies. It’s somewhat crude at the moment, analyzing expression panels and combinations of mutations. The biology needs to become much more predictive. Also, a practical problem with patient-specific therapies is that the clinical trails become harder to assess as the size of patient pool targeted for each ‘custom’ therapy study shrinks. So additionally, our testing regimes will have to experience a significant revision as well. Most researchers seem to recognize this but advancing each step has been a hard slog.

HIV therapeutic research was easier in this regard (Not that is wasn’t the state of the art at the time). The number of targets was smaller and the relatively small number of drugs available were validated individually before testing in combination.


(Peaceful Science) #14

Caution is warranted. Agreed.


#15

Where are my #$%#$&!! manners?

Congratulations on the paper!


(Chris Falter) #16

Dr. Swamidass,

Congratulations, indeed!

When uncertainty is prominent, many researchers regard Bayes’ Theorem as a way to make inferences and decisions. While I could have spent a few hours analyzing your Xenosite code published on bitbucket.org, it seemed more reasonable just to ask you: did you rely on Bayesian reasoning in this project? If so, how?

Thanks!

Chris Falter


(Peaceful Science) #17

Sort of.

We use neural networks, which are designed to fit the posterior probability distribution (the prediction) of the mutation labels given their descriptors. This is a type of Bayesian method called MAP, which you can read more about here https://en.wikipedia.org/wiki/Maximum_a_posteriori_estimation and here https://www.cs.cmu.edu/afs/cs/academic/class/15782-f06/slides/bayesian.pdf)

We also use Expectation Maximization algorithm in conjunction with the neural network, to determine the labels. EM is a semi-bayesian method, https://en.wikipedia.org/wiki/Expectation–maximization_algorithm too.

Over all the method is definitely of the Bayesian school (rather than frequentist) but it is not a full Bayesian treatment.

Well that was a fun technical question =).


(Jon Garvey) #18

Joshua

Let me add my congratulations here on your paper, which indeed looks likely to bear good fruit.

But I’m still having some trouble getting my head round the concept of “tumours evolving” rather than “populations of organisms evolving new susceptibilities to damage.” It sounds to me to be a metaphorical use of “evolution” that potentially functions to redefine mutations “deleterious to organisms” (the commonest type, because breaking stuff is easy) as “beneficial to tumours”.

It reminds me of Dawkins’ metaphor of the “selfish” gene as the true locus of evolution, which ticked all the population genetics boxes until the primacy of the cell in gene expression began to show it to be an inversion of the real situation.

Our evolutionary theories, after all, are about variation and selection in reproducing populations, leading to differential reproduction, are they not?. It’s not that tumours are not species - but that they are not true reproducing populations. Instead they are aberrations of cell-lines which even themselves are not loci of evolution, unless one has a very atomised view of eukaryote biology. After all, we don’t regard villous cells as “successful” because millions are produced daily, and Betz cells as “unsuccessful” because there are only 50,000 of them. We rightly see their role as subservient to the good of the true functional entity, the organism. How then can one rationally discuss the biological “fitness” of tumours, or even tumour-cells?

Since many BioLogos readers will have no medical background, let me briefly describe tumoursfor them. If a cell line - for example, melanocytes - has a particular genetic propensity, and is subject to the right environmental influences - for example, excessive UV - in just a small proportion of the susceptible individuals one, or a few, of the millions of melacocytes in the body will break free of the usual physiological regulation. If it also bypasses the body’s immune defence mechanisms, it may clone to form a malignant melanoma.

This is deleterious to the parent cell line of melanocytes, because they are destroyed by aberrant cells, deleterious to the organism (the true locus of variation), and ultimately deleterious to the wildly reproducing tumour cells, because they die with the patient… though presumably neutral theory correctly predicts how and why the particular genetic markers involved exist in the human population.

If one may treat tumours as a quasi-species “benefiting” from mutations, and so evolving, then equally one can talk of immune cells “evolving” because genetic patterns of auto-immune disease cause them to proliferate. But is that not ultimately a misleading view down the wrong end of the telescope?

So that’s my first problem. My second is that in rejecting ID arguments regarding evidence for design (not sure which ones - is it the alleged rarity of beneficial mutations, in which case the validity of “tumours” as a true locus of evolution becomes crucial?) you have also apparently rejected any actual divine involvement:

…or regularly require the direct intervention of God to initiate and be sustained. I’m not sure which option is harder to believe.

That seems to be a theological, not a scientific, statement. It always plays well to deny the involvement of God in anything harmful (though of course in the Bible God does actively send tumours, albeit bubonic rather than malignant ones), but the question needs to be argued, not assumed. If it is hard to believe in principle that God (or why not the devil, if one is a believer in fallen creation?) would be associated with these genetic changes, then one is saying that they are excluded from God’s providence.

More specifically, in the context of the belief called “Evolutionary Creation”, in which “evolution is God’s means of creating life”, one is saying that not all evolution is God’s creation, but only some.

In which case, one needs to state clearly what other “demiurge” has its muddy paws in the process of evolutionary creation, and presumably be able to have some emprical way of discerning which parts of creation are designed by God, and which by this other agent (chance, maybe?). That would, it seems to me, only be a particularly subjectively discriminatory form of Intelligent Design.


(Peaceful Science) #19

Good questions Jon! Thanks for the note…

I see your objection and am sympathetic because I held it for a long time too. It is easy to dismiss all we have learned about cancer and its relation to evolution as an example of things “breaking down,” but look at this from the point of view of cancer cells “evolving” is perhaps the dominant paradigm, and is a more accurate approach for a few reasons.

  1. Cancer cells are not “less” functional, as if they were broken. In fact malignancy requires several (some estimate up to 15) often convergent genetic changes (i.e. angiogenesis, cell-adhesion, etc.). The preferred term is “disfunction” because it recognizes correctly that cancers are functioning inproperly (not failing to function), and this is often achieved with neofunctionalization,at a molecular level, something that many ID people think is impossible. This fits the evolution paradigm better the broken paradigm.

  2. Cancer cells clealry adapt to their environment and this is fundamentally important to treatment, because they develop resistance to drugs by evolutionary processes.

  3. As a model system for evolution, it is particularly useful because the genetics of cancer match humans better than any other model. There are whole classes of mutational systems (e.g. splicing variants) that can cause cancer but are not really at play in microbial systems.

  4. All the mathematical machinery of population genetics and neutral theory seem to work exactly as we expect they would on cancer. So perhaps it is an analogy (because cancer is not an independent organism). Though, some versions of cancer do function like transmissible parasites (https://en.wikipedia.org/wiki/Canine_transmissible_venereal_tumor) but that is atypical.

  5. Finally, the reasoning we use is identical to evolutionary reasoning. We use data in the present to make inferrential statements about the past.

Now, you are are right, cancer is not exactly evolution, because new species are not evolving. That is where the analogy breaks down. I, rather, think of each tumor as its own independent evolution experiment (and also a tragedy for the patient that we want to cure).

I think you are missing what I meaning. What I am saying is different.

If many ID arguments about neofunctionalization and molecular convergence being impossible are true (as many ID proponents are convinced), how do we explain neofunctionalization and molecular convergence in cancer? Clearly it is the same biological system, and we are seeing neofunctionalization and molecular convergence, and all the same genetic patterns in cancer tumors that we see in, for example, humans the the great apes.

In the case of evolution, we look at this data and some ID proponents conclude that it must have required God’s (thought they would say “designer”) direct intervention somehow (from tinkering to special creation).

In the case of cancer, the data looks very very similar. If the ID proponents are right aboutevolution, why would we conclude anything different here?

To take the theology out of it, i should have said,

or regularly require the direct intervention of [an intelligent designer] to initiate and be sustained. I’m not sure which option is harder to believe.

The point is not about theology (though it certainly raises theological questions) but is a question of how the ID scientific logic is applied in two places (evolution and cancer) where we have nearly identical genetic data.


(Phil) #20

Good explanation. In layman’s terms, this is why another round of the same chemo that did well the first time, will not work as well the second, and why recurrent cancer is tougher than the primary. You can kill the easy cells, but the more resistant ones take over and grow.