Aaargh! Physicists! Again!

A while back, two physicists, Paul Davies and Charles Lineweaver, announced their explanation for cancer with a novel theory, which is theirs, that cancers are atavisms recapitulating in a Haeckelian reverse double backflip their premetazoan ancestry. They seemed very proud of their idea.

I was aghast, as you might guess. They even claimed that human embryos go through a fish/amphibian stage with gills, webbed feet, and tails in a pattern of Haeckelian development. They do not understand evolution, development, or cancer, facts that were apparent even in the absence of their admission that they had no prior knowledge, and it was freaking embarrassing to see two smart guys with a measure of legitimate prestige in their own specialties charging off into another discipline with such crackpot notions.

Now they've done it again, repeating the same claims all over again. And worse, they've now published it in the journal Physical Biology, under the title "Cancer tumors as Metazoa 1.0: tapping genes of ancient ancestors".

The genes of cellular cooperation that evolved with multicellularity about a billion years ago are the same genes that malfunction to cause cancer. We hypothesize that cancer is an atavistic condition that occurs when genetic or epigenetic malfunction unlocks an ancient ‘toolkit’ of pre-existing adaptations, re-establishing the dominance of an earlier layer of genes that controlled loose-knit colonies of only partially differentiated cells, similar to tumors. The existence of such a toolkit implies that the progress of the neoplasm in the host organism differs distinctively from normal Darwinian evolution. Comparative genomics and the phylogeny of basal metazoans, opisthokonta and basal multicellular eukaryotes should help identify the relevant genes and yield the order in which they evolved. This order will be a rough guide to the reverse order in which cancer develops, as mutations disrupt the genes of cellular cooperation. Our proposal is consistent with current understanding of cancer and explains the paradoxical rapidity with which cancer acquires a suite of mutually-supportive complex abilities. Finally we make several predictions and suggest ways to test this model.

Oh. My. Gob. So…much…wrongness.

I read the paper. I cringed. This blogger read the summaries. He cringed. I think anyone who is the least bit informed about biology will feel the same way…but this crap will continue to get published in legitimate journals because…because…hey, physicist! They must know something we don't! (Well, they do know things we don't, but we know things they don't, and knowledge of cosmology doesn't translate into knowledge of molecular biology. Or vice versa.)

The conceits of the paper are 1) a lack of knowledge about cellular evolution that allows them to posit evidence-free scenarios; 2) peculiar notions about molecular biology that allow them to imagine whole invisible networks of primeval genes lurking as atavisms beneath the polished exteriors of urbane and civilized modern cells; and 3) bizarre misconceptions about cancer causing mutations that they can't back up with a single specific example.

So let's start with the first objection, the weird evolutionary history enshrined in the title. They postulate a step in evolution just above the colonial stage, with groups of cells having marginal specializations — which is reasonable, up to a point.

The transition from unicellular to complex multicellular organisms took place over an extended period starting at least 1 billion years ago (Hedges and Kumar 2009). Importantly, ‘advanced’ metazoan life of the form we now know, i.e. organisms with cell specialization and organ differentiation, was preceded by colonies of eukaryotic cells in which cellular cooperation was fairly rudimentary, consisting of networks of adhering cells exchanging information chemically, and forming self-organized assemblages with only a moderate division of labor. These proto-metazoans were effectively small, loosely-knit ecosystems that fell short of the complex organization and regulation we associate with most modern metazoans. In short, proto-metazoans, which we dub Metazoans 1.0, were tumor-like neoplasms.

Aaargh. That last sentence. It's like announcing a theory of human evolution which has as a premise that chimpanzees are mentally retarded people — it manages to insult and mischaracterize both chimps and people with mental handicaps. No, early metazoans were healthy, functional, successful organisms. Neoplasms are abnormal masses of tissue produced by excessive reproduction of cells with broken regulatory machinery. You don't get to declare the relevance of your analogy by simply declaring both sides equivalent; there is no reasonable, evidence-based rationale for declaring early metazoans to be a bunch of tumors.

Davies and Lineweaver don't provide any evidence for their evolutionary history, either. It's really a simplistic just-so story in which they claim metazoan precursors were just like cancers so that they can claim that cancer uncovers a lurking atavism which proves that metazoan precursors were just like cancers. It's so circular I got dizzy.

Which leads us to their problem #2: 'atavisms'. They've got this vision of wedging poor old Darwin into supporting a hierarchy. Like Haeckel's version of the story, we're built of accumulated layers of new traits, where old ones are buried and fossilized beneath new genes, and all it takes is a little erosion to expose well-preserved relics. It's all terminal addition, with a little nod to some modification of earlier stages of our evolution.

It is, however, in the nature of Darwinian evolution that life builds opportunistically on what has gone before. The genetic apparatus of the new Metazoa 2.0 was overlain on the old genetic apparatus of Metazoa 1.0. The genes of Metazoa 1.0 were tinkered with where possible, and suppressed where necessary. But many are still there, constituting a robust toolkit for the survival, maintenance and propagation of non- differentiated or weakly-differentiated cells—‘tumors’—and when things go wrong (often in senescence of the organism) with the nuanced overlay that characterizes Metazoa 2.0, the system may revert to the ancient, more robust way of building multicellular assemblages—Metazoa 1.0.

Aaargh. No. Genes that are suppressed decay and are lost, not lurking. Genes that remain and are tinkered with by mutations acquire new functions, lose old ones, and are assembled into new, coevolving networks. If they're still there, they're still part of the current regulatory pathways; they're not in a separate 'layer', they're not waiting, unmodified, to blithely re-enact ancestral states. No, really, you can't take one of your cells, switch off a few genes, and set it free in the ocean to swim off and follow its primitive lifestyle. Cancers are not dreaming of protistan independence.

Again, they're playing the same trick: postulating a condition that would make their model work, because it would make the model work, not because they actually have evidence that this is how gene networks function.

Along the way, they try to argue with standard models of cancer formation which assume, for instance that cell proliferation is a product of broken regulatory brakes, not activation of a sleeper program to reinvoke an ancestral state. Davies and Lineweaver point out that cancer cells actually have patterns of integration and communication that promote survival — how could that be if they were merely rogue cells rampaging madly through the body? I wanted to scream at them, "because they are slightly modified metazoan cells still, you blinkered crackpots!" Cancer cells can execute growth-promoting activities like secreting signals that encourage a blood supply to infiltrate the tumor because they are intrinsically multicellular, not because they are reverting to a cunning barbarism.

They also object to a model they call "internal Darwinism": that cancer cells have the suite of traits that they do not because of some internal coherent plan, but because they experience random mutations, many of which kill the cancer cells, but we only see the successful combinations of traits that produce proliferative, invasive tumors. And they claim to have evidence against that model. They don't.

Our explanation of cancer as an atavism that short- circuits the Metazoa 2.0 regulatory system and unleashes the suppressed Metazoa 1.0 system receives support from the amazing pleiotropy of some enzymes, and, as has been realized recently, some micro-RNAs (miRNAs). Thus the enzyme COX-2 and the miRNA known as miR-31 have been found to control not just one, but a collection of tumorigenic factors. Such remarkable efficiency and economy would be deeply puzzling if it arose from a few decades of internal Darwinism, but makes perfect sense if it had been honed by evolution over an extended period of time to form an optimized package that constitutes a type of on–off switch for a set of previously adaptive traits.

But…but…pleiotropy is an essentially universal property of regulatory genes! We expect this kind of widely interacting behavior. And why would you consider expression of an interaction between two components of a regulatory system to be a property of "previously adaptive traits" rather than a property of currently functional and adaptive traits? This kind of argument resolves nothing in their model.

Let's now consider that third problem I mentioned, that they don't seem to be able to discuss how known cancer mutations work, and don't give any specific examples of atavistic gene circuitry exposed by a modified oncogene. I'll be specific; let's use Rb as an example.

Rb is a known oncogene, that is, a gene that when modified or broken can cause one step in the path towards cancer. It's normal role in healthy cells is as a regulator of the cell cycle.

Dividing cells follow a cycle. Most cells are in G1 (Gap 1), doing what cells do, and then under control of clock-like changes in specific genes, they can enter the S (synthesis) phase, when their DNA is replicated, followed by a G2 phase (gap 2), and than an actively dividing mitotic or M phase. Each of these phases has a checkpoint where a battery of proteins survey the state of the cell and either permit the process to proceed, or block it if there are problems. In extreme cases, the checkpoint proteins can determine that the cell is so irreparably damaged that the only option is suicide, and the cell will self destruct.

This is a process that cancer needs to disrupt if it is to continue; cancer cells typically have damaged DNA or aberrant signals flying everywhere that ought to be triggering all kinds of alarms in the checkpoint system, and either stopping cell division immediately, or activating repair mechanisms that fix the damage, or just killing the corrupted cell immediately.

One of the most critical points in this cycle is called the R or Restriction point. Prior to this point, the cell is sensitive to external signals that can induce cell division; after this point, the cell no longer pays attention to those signals, because it is on a rigidly programmed track towards completing cell division. This is that last fateful moment of decision before the cell commits to dividing.

Standing at this point is an essential guardian of the cell cycle, pRb. This protein is an inhibitor of cell division, acting as a tumor suppressor gene. It's the guard at the gate, and it must be satisfied that all is well in the cell before it will allow division to continue. It's default mode is to stop cell division, but it recieves signals from a wide array of pathways that can tell it to stand down and let the process continue. Trust me, control of this gene is complicated because it is so essential to well-regulated cell division: look at it here, standing sentry just above the yellow R point, with all these other pathways talking to it:

I think you can see how this gene can contribute to cancer when it's defective. Shoot the guard, open the gate wide, and allow cell divisions to proceed unchecked.

What I don't see, and what doesn't fit the Davies/Lineweaver model, is where the emergent atavisms are. The components of the cell cycle that are disinhibited by loss of this protein are not hidden away and are not unused, primitive versions of cell cycle regulators; they are simply the contemporary regulators with an essential limiting factor removed.

This is not to say that the evolutionary history of the gene is unimportant. There have been several phylogenetic studies of Rb; it's present in most eukaryotes (and some homologous sequences have been identified in the Archaea!), single-celled as well as multicellular, but it does show increasing complexity in its function in multicellular organisms. It is simply not the case, however, that you can find "layers" of Rb function that allow you to peel away modern functions to expose an antique Rb that makes it revert to an ancient pattern of behavior.

Let's let Davies and Lineweaver get even further from science. Why should we like their model? Because it's more optimistic than those poopyhead biologists' ideas!

Given cancer’s formidable complexity and diversity, how might one make progress toward controlling it? If the atavism hypothesis is correct, there are new reasons for optimism. The postulated toolkit of Metazoa 2.0, although admittedly complex, is nevertheless a fixed and finite feature of multicellular life. The number of tools in the kit is not infinite. What one cancer learns cannot be passed on to the next generation of cancers in other patients. Cancer is not going anywhere evolutionarily; it just starts up all over again in the next patient. Although cancer may seem like a perpetually moving target, a given cancer has a strictly limited set of atavistic possibilities open to it. Thus, cancer is a limited and ultimately predictable adversary. This understanding of cancer as a limited atavism should engender optimism among oncologists. The anticipated precision of personalized drug therapies will not be infinite. This view contrasts sharply with the open-ended possibilities for cancer implied by the ‘internal Darwinism’ model.

Scientists shouldn't be looking for optimism, they should be searching for the truth, which is sometimes going to be grim. So what if the 'internal Darwinism' model implies an intimidating number of possibilities? It is what it is. Every cancer is different, every cancer is complicated, and waving your hands and pretending that there is an ancestrally-derived unity of mechanisms under every single cancer doesn't make it so. Davies and Lineweaver are going to have to do better than parading decades-old evolutionary misconceptions at me to persuade me of their case.

Cao L, Peng B, Yao L, Zhang X, Sun K, Yang X, Yu L (2010) The ancient function of RB-E2F pathway: insights from its evolutionary history. Biol Direct 5:55.

Davies PCW, Lineweaver CH (2012) Cancer tumors as Metazoa 1.0: tapping genes of ancient ancestors. Phys. Biol. 8 015001-015008.

Takemura M (2005) Evolutionary history of the retinoblastoma gene from archaea to eukarya. Biosystems 82(3):266-72.

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I guess the nice thing about their theory is that it is trivially falsifiable. Drop a neoplasm in the ocean, if it survives, I guess they were right. If you want to get all nitpicky, you might say we need to replicate an ancient ocean, which is fair, but probably not too difficult to do. Since the damn thing will probably die no matter what we do, without the support of the human body, we can pick an ancient ocean environment that is as favorable as possible to these silly fellows.

Why is it always the physicists who think that they know everything about every discipline? I think it's time we biologists come up with some crackpot physics!

Hmm. What's the matter PZ? You all of a sudden do not believe in your fellow scientists? Awww. What a shame. No one believes the 30,000 scientists wh say global warming is a scam either. The UN keeps silencing them so that they can get more of OUR money.

To this day, no one really knows how cancer is formed. Cancer can be caused by a variety of scenarios from environmental to gentic. There is probably no one certain thing that causes cancer.

By Fifty Three Pe… (not verified) on 20 Nov 2012 #permalink

Off subject. Newsweek is doubling down on the stupid with another Eben Alexander article. Their corpse is getting very twitchy.

Fifty Three Percenter: PZ is dismissing claims not based on peer-reviewed evidence, just like people dismiss anti-climate change cranks who also have no peer-reviewed evidence. As for the causes of cancer, we know more about that than you think, which is why I recommend that you read a bit about the subject before unleashing such idiocy upon this blog.

Well, this is ridiculous.

There clearly is an "internal Darwinism" going on, as plenty of people could tell you, such as those with remission, resurfacing disease and the experience of a chemotherapeutic agent no longer working. The high mutation rates in cancers is one of the main problems.

Slight disagreement with PZ here: Sure, every cancer is different, but observations do show that there are a number of particularly common defects that trigger the malignant growth. Some cancers even have particular trademark defects associated with them. Still, that is nothing like what these guys are proposing, especially since it doesn't remove the cancers' ability for mutational adaptation, the "internal Darwinism" going on.

Oi, A. R, how did you get an actual picture associated with your handle? Or do you have an account with this website or something and that is why? Just from the comment-section alone, I can't tell the difference, I fear. Thanks!

@A. R: Some physicists are arrogant know-it-alls. In other news: water is wet, bears defecate in the woods, and Generalísimo Francisco Franco is still dead. There is some truth to the assertion that physics is at the base of other sciences. What happens is that the physicists who get into crackpot science in other fields (it's not just biology; for example, a physicist led the BEST consortium that was supposed to correct the errors of climate scientists who extract trends from temperature records, only to find that the climate scientists were right) forget the extent to which models of complex phenomena have to be simplified in order to be useful. In principle, someone with lots of time and computational resources could construct a purely physical model of a biological system. (The opposite is not true; indeed, most areas of physics have no need of biology.) In practice, such a model would have so many variables and parameters as to be useless.

You can also blame it a bit on Richard Feynman, who dabbled a bit in areas outside of physics, with varying degrees of success (including a foray into biology where, as he tells the story in his memoirs, a rookie mistake in his lab technique cost him a shot at making a fundamental discovery). All of us who go into physics hope to be the next Feynman. Most of us soon realize that we aren't of that caliber, and that none of our colleagues are either. Davies and Lineweaver apparently never came to that realization.

By Eric Lund (not verified) on 21 Nov 2012 #permalink

As usual, xkcd has a comic commentary:

I'd like to see your fellow Nat Sci blogger Orac take a crack at this too. That would be fun.

By Nick Theodorakis (not verified) on 21 Nov 2012 #permalink

Oops I meant Nat Geo blogger

By Nick Theodorakis (not verified) on 21 Nov 2012 #permalink

Just one minor quibble, PZ, Rb is a classical tumour suppressor and not an oncogene. Loss of function is accompanied by enhanced growth of cells bearing mutant copies.

By Ankur 'Explore… (not verified) on 21 Nov 2012 #permalink

Thanks PZ! Some say confusion is the pathway to knowledge but a good argument is more satisfying.

By Frog Counter (not verified) on 21 Nov 2012 #permalink

Shades of Hoyle & Wickramasinghe. I suppose that humility isn't a necessary requisite for a scientist.

By Roq Marish (@Roqsan) (not verified) on 23 Nov 2012 #permalink

It strikes me that these guys are merely taking mainstream understanding of cancers and adding a layer of bullshit about "atavisms" to make it sound as if they came up with something new.

Cancer cells need to do three things to be cancer cells - 1) proliferate (but if they only proliferate they're "benign" tumor cells, which are not necessarily harmless but are not fully malignant), 2) fail to differentiate normally, and 3) interfere with normal bodily function and integrity in some way. If cells aren't doing those three things, or about to do those three things just as we catch them, the patient doesn't have cancer.

Putting aside lymphoma and leukemia, in patients with access to modern medical care, common cancers need to become invasive and metastatic to do real harm. (In patients without such access a benign neoplasm that could have been cured with surgical excision may cause real harm - "benign" means not invasive or metastatic, rather than "harmless").

Since invasive/metastatic cancer cells express genes in an abnormal way that causes them to become more motile and less cohesive and regulated than normal cells, and outcompete individual normal cells at the expense of the organism as as whole, they do, as a trivial observation, express a suite of genes that makes them analogous to invasive single celled organisms in some ways.

That's not the wrong part.

The wrong part is expressing a valid (and rather obvious and widely used) analogy as some sort of magical "atavism" idea.

Since there is no preview function here, I apologize for any typos or fouled up html formatting, should any be apparent.

I'm new to this blog and although I claim scientist status, cancer and tumors are way outside my expertise. I wanted to point out what I believe to be a vague Python reference in the first paragraph...the theory, which is theirs (and what it is, too) bears resemblance to Ms. Anne Elk's theory of brontosaurus's (thats A-n-n-e Elk, not an elk).


By Bishams gramma… (not verified) on 24 Nov 2012 #permalink

What concerns me is that well-educated people who don't understand essential concepts like this are going to be running profit-hungry synthetic biology companies in the near future.

As a physicist, I really hate it when physicists, esp. theorists, are all like "I'm a physicist, I therefore must know something about this." They do this to their fellow physicists too and it isn't pleasant. I feel your pain.

However, my last biology class was high school freshman biology, and I have some serious misconceptions that are often only remedied by reading science blogs. Just from remembering that we have vestigial organs and whales have leg bones (right? I hope I'm not making that up), their "cancer is just activating dormant genes" doesn't sound too crazy.

Now, unlike me, they claim to actually know some biology and it's pretty inexcusable to publish rubbish.

It just seems like nonsense to me. Cancer's semi-mysterious survival traits aren't adaptive, and they wouldn't be for any multicellular organism as far as I can tell.

In my view, cancer is such a big word to hide our ignorance. Behind this word lurks hundreds if not thousands of different diseases. It's like saying having "anemia" in a recent past or "he is just damn crazy" in a hopefully distant past. Each cancer has it's own story, ultimately genetic, probably involving hundreds of genes interacting together.

This being said, many "outdated" genetic programs are still out there which express themselves in some people with such interesting things like:

Vestigial tail -> coccyx bones (and sometimes a real tail, google it to see examples)
Appendix -> once useful in a distant vegetarian past, quite variable in humans
Many muscles:
Muscles to move the ear (like the wolf): the muscles still exist, attached to the ear but can't move it. However, some humans still retain this capacity
Muscles that can flip the coin on a belly: some humans still have it
and many more muscles that exist as remnants only in most people (e.g. tendon) to fully functional muscles in some. These "useless" tendons remnants can be used for graft by a surgeon. (like the plantaris muscle)
Plica semilunaris -> vestigial structure remnant of the nictitating membrane still present in all of us (useful when our ancestors were aquatic!
Archaic reflexes:
-> any infant examined by a doctor gets checked for many archaic reflexes of no particular use today
-> goose bumps: maybe useful in a not so distant furry past
when you needed to raise all your hair to look bigger to an agressor, not so much now
-> extra nipples or breasts that line up ( I have seen people with that personally) -> truly useless. Not talking about the male nipples... hard to find a useful need for them...

The idea is that all these "outdated" genes/programs are out there in our population. Most of them are not lethal, mostly neutral, so they persist as genetic variability in the population. This variability when combined can allow older structures to reappear.

I wonder how can one be certain that such process could not be involved in some cancers... in other words genes used here and there for a modern function, could function in an "older" way when combined in an individual.

For the physics part now... I agree that the complexity of biology by definition surpasses physics. For example, the properties of an hydrogen atom are not the same when present in a water molecule. When you combine hundreds or thousands of atoms in a protein you can not predict on atomic physics alone what will happen. New properties emerge with each level of complexity. In that sense, the behaviour of the electrons in a complex molecule is different than in a single atom. Physics need chemistry and biologist to figure out what happens at a "macro" level. It is too easy to say: well the neutrons and protons essentially do not change and the electrons are so tiny they do not count in the properties of the atom...

Distressingly they have a large PSOC grant Though the PSOC idea is itself very conceited - physicists have already made contributions in cancer biology when working closely with cancer biologists.

Even though it seems that they were wrong - "I couldn't possibly comment" - they have at least tried to come up with a different point of view. Most breakthroughs seem to come from people who differ from the conventional wisdom or who techically are acting "off expertise." Sadly a lot of crackpot ideas come from the same source, but this does not mean they should be suppressed. They should be encouraged even if most are wrong. Now about that patent clerk (second classs) in 1905 who needed a good haircut. Now he had an unacceptable idea, but was proved right and was rewarded for his unconventional breakthrough - he was promoted to patent clerk (1st class)...amongst other things.

By Philip D Welsby (not verified) on 27 Nov 2012 #permalink

This is probably a good time for me to send in my earth-shattering physics paper on "Why Quantum Physics is Wrong: A Biological Explanation." I'm sure that they'll be just thrilled to see it. /snark

The fundamental fallacy of the physicists seems to be misunderstanding a basic tenet of cancer cell biology: that cancer cells evolve.

*Evolve*, no *devolve*. Once they shed inhibitions of growth, they have to undergo several OTHER changes before they become full blown metastatic cancer. What causes these changes? Selective pressure by the immune system. Cancer cells are genetically unstable and mutate very frequently as they divide. Most of the cells are caught by the immune system and die; sometimes this happens to the whole tumour and we never know we had a close call.

But if one survives and beats the immune system's own surveillance system, you have the beginnings of a real carcinoma.

I'm much more likely to put stock in the latest theory, the "cancer stem cell theory" then this. (It states that most cells in a tumour are nonviable, and a very small population actively dividing cells within the tumour keep it growing and spreading. How do you identify those cells over the masses of nongrowing ones? That's the million dollar question...)

By ArchTeryx (not verified) on 28 Nov 2012 #permalink