Tissue Organization Field Theory

It’s been a while since I brought everyone up to date on the progress of my Ecological Development course, because I’ve been busy. So have the students. After our spring break I subjected them to the dreaded oral exam, which actually isn’t so bad. I tried to engage them less in an adversarial role and more as a quiet conversation between two people on science. Some students took to it easily — the more outgoing ones — others were noticeably nervous, which was OK, and I hope they learned that it isn’t that terrifying to have a discussion with a mentor.

Then the next few weeks were a mad whirl of horrible things done to babies: teratogens, endocrine disruptors, multi-generational epigenetic inheritance, all that fun stuff. We wrapped up with the depressing stuff for me, although the young’uns were more sanguine, I think. We talked about adult onset developmental diseases (it’s good to look at heart disease through the lens of developmental biology), aging, and cancer. Next week they get some time off, because I’m being drawn away to a conference on the east coast, but they’re supposed to spend it preparing for their final presentations, which will consume the last two weeks of class. And then we’re all done. School’s out for summer!

I’m going to say a bit about our last class discussion, because it got into some interesting territory and reflects the theme of the course well. We talked about that theory mentioned in the title of this article, and the origins of cancer, and to do that I have to give you all a little background.

Tissue Organization Field Theory (TOFT) is an alternative to what is sort of the dominant paradigm in cancer biology, the Somatic Mutation Theory (SMT). I have to say “sort of” because what I get from the literature is that SMT is more of a working assumption, and that cancer biologists are open to new ideas. The SMT is a useful molecular perspective on carcinogenesis. It postulates that cancer is a cellular disorder in which the genetic material has been perturbed to produce a lineage of cells with aberrant characteristics, that if we want to figure out what the primary cause of a cancer was, we can trace it back to a somatic mutation, or a change in a critical gene or, more likely, multiple genes, that lead to uncontrolled proliferation. So we pursue oncogenes, genes that have the potential to acquire mutations that trigger cell division or bypass control points, and tumor suppressor genes, protective genes that, when damaged, remove essential regulators of growth.

So, under the SMT, cancer is a disease caused by the progressive accumulation of mutations in cells of the body, as they divide. These mutations gradually strip away the normal restraints on cell division, and on immune system recognition, and on cell death activation, etc., etc., etc. until you have a rogue cell that can seed the growth of a massively disruptive tumor.

And it’s not wrong! Cancer biology has been immensely productive in identifying the enabling mutations, and even developing treatments that specifically target molecular agents of cancer. We know that somatic mutations are a routine part of the progression of cancer, and we also know that there heritable alleles that can affect the likelihood of the disease. The SMT is a tool to explain many of the phenomena of cancer, and it’s not going to just go away. It’s also a tool that is amenable to a reductionist approach to cancer biology, and is well-adapted to the utility of molecular biology.

Tissue Organization Field Theory is an alternative explanation for the origins of cancer.

TOFT argues that the focus of the SMT on single cell events is inappropriate and misses a whole range of effects at the level of tissue organization, effects which are more important in creating a pathological environment in which those mutations can accumulate. Further, it gets into field theory, which is important in developmental biology but isn’t exactly the subject of common conversation. Here’s one standard definition of a field: “a morphogenetic (or developmental) field is a region or a part of the embryo which responds as a coordinated unit to embryonic induction and results in complex or multiple anatomic structures.” If that’s not helpful — and it probably isn’t, we’d have to go over a textbook if we wanted to explain developmental field theory — here’s a diagramatic metaphor. Do you see the field in this picture?

There’s something special about part of that image, but it’s not that the individual subunits are intrinsically different — it’s tied up in the relationships between the central set of blocks and the blocks outside of it. There’s something different going on with a subset of the blocks, but it’s not necessarily best described by explaining the details of single blocks, but is more easily explained at a higher level, as properties of a tissue within a tissue. Of course, what will eventually happen in a developing organism is that those central blocks will express a unique pattern of genes, so eventually it’s identifiable by molecular markers, but the field first arises in a sea of genetically and epigenetically uniform cells.

Another important property of a field is that it is not itself uniform. It’s going to acquire complex spatial properties over time. Insect limbs, for instance, arise from a disc-shaped field with extensive patterning information within them, so the central region will become the distal tip of the limb, and there is information that is interpreted as polar coordinates that specifies what portion of the limb is anterior, posterior, medial, and lateral (the limb is not a uniform cylinder). Similarly, vertebrates have a limb field represented in the limb bud, with gradients of morphogens specifying the orientation of the limb, and with re-expression of Hox genes used to specify longitudinal positions. Hox genes in a limb field are interpreted in different ways than Hox genes along the body axis, obviously.

The key factor here is that in field theory cells are not simply independent units — they are part of a larger assemblage, a tissue, that has complex fates that are not easily summarized by individual gene expression. They have to be understood as a network.

That’s the first thing to remember: TOFT is treating a cancer as a field, with field properties, which are not adequately described if you only look at cancer as a collection of autonomous cells all doing their own thing at the command of their broken genes. Aberrant disruption of the field can produce aberrant structures without requiring any genetic changes.

This is the difference between a mutagen and a teratogen. The effects of a mutagen are caused directly by damage to the structure or sequence of DNA; they produce heritable changes to the cells of an organism. Teratogens, on the other hand, are not necessarily mutagenic at all — they disrupt the normal pattern of development without changing genes at all. Thalidomide babies, for example, had some extreme morphological changes, like phocomelia or truncated limb development, but those are not heritable, and the people affected by thalidomide can grow up to have normal, healthy children.

TOFT argues something similar, that there is a disruption of a tissue that initializes aberrant growth, that may then be an enabling precondition for the accumulation of mutations. One piece of evidence for this is a set of experiments on tissues, illustrated below.

Most cancers arise in epithelial tissues, like the sheets of cells that line glands or your organs, in large part because those are the cells that divide most frequently. These epithelial cells, also called parenchyma, do not typically grow in isolation, but on a substrated of connective tissue, extracellular matrix, and other cell types, called stroma. The stroma supports and signals the overlying epithelium, and vice versa, and together they make a coherent functional tissue.

The theory suggests that cancers can arise in epithelia by way of disruptions in signaling in the stroma. A carcinogen could distort the interactions between stroma and epithelium at the level of the stroma, and the epithelium then goes nuts and proliferates to produce a pre-cancerous mass.

One test of the theory would be to separate stroma and epithelium, expose the stroma to a short-lived teratogen, and then after the teratogen was washed out, re-associate the two and determine whether there was an increase in the frequency of cancers in the epithelium, which has not been exposed to teratogens.

The experiment has been done. Here are the results for rat mammary gland tissue in which the epithelium was exposed to the solvent vehicle but no N-methyl nitorsourea (a potent mutagen), while the stroma was soaked in NMu, labeled VEH/NMu. The numerator describes the epithelial condition, and the denominator is the stroma condition, so NMu/NMu means both were hit with the mutagen, VEH/VEH means both were exposed only to the vehicle, and NMu/VEH means the epithelium was poisoned with NMu, while the stroma was not.

There’s an awfully strong positive correlation between exposing the stroma to mutagens and getting tumors, and a negative correlation with exposing epithelia to mutagens and tumors.

You want more evidence? Here’s a very interesting experiment. Start with aggressively metastatic melanoma cells from a human patient (labeled in green, below). Inject them into a completely different environment, the neural crest pathway in a developing chick embryo. Surprisingly, if you accept the SMT, the cancer cells calm right down and are conditioned by their environment to participate in normal development in the chick and get incorporated into the facial cartilages and sympathetic ganglia.

I suspect those melanoma cells do carry somatic mutations, and are not actually “cured” of a predisposition to cancer. What the experiment says, though, is that environmental influences are extremely important in regulating the behavior of these cells, and that modifying the cells communicating with the cancerous cells can have a profound effect on how they act.

Note that this is not a pathway to a cure. It’s all well and good to say that if we could break up a tumor, separate the individual cells and put them in a more nurturing, embryo-like environment, they’ll stop acting up and resume normal, regulated growth, but if we could do that, slicing out the tumor and tossing it in an incinerator would also be effective. The problem is that in a human patient we do not and cannot have such precise control of the micro-environment of the cancer, and in fact, the tumor itself is a kind of bubble of micro-environment that actively reinforces cancer growth.

My students and I read a paper from Carlos Sonnenschein, who is a major proponent of TOFT, as well as our textbook summary. The paper was titled The tissue organization field theory of cancer: a testable replacement for the somatic mutation theory. They’re a smart bunch, and they see the promise of the idea, in part because this whole course is about thinking a level above reductionist cell biology, but they also found the word “replacement” off-putting. It doesn’t invalidate everything about the SMT, but it does support an important alternative route for carcinogenesis. They also weren’t impressed by the rather aggressive insistence by some TOFT proponents that they have the One True Explanation, and that their observations are sufficent to explain cancer — we came up with a few alternative interpretations of their own favorite experiments that they haven’t nailed down completely just yet.

One thing that amused me is that the class consensus actually converged on the views of another paper by Bedessem and Ruphy, which I did not assign them to read, largely because of its more philosophical argument (I’ve focused on empirical/experimental papers in the class). This is how I feel about it, too.

The building of a global model of carcinogenesis is one of modern biology’s greatest challenges. The traditional somatic mutation theory (SMT) is now supplemented by a new approach, called the Tissue Organization Field Theory (TOFT). According to TOFT, the original source of cancer is loss of tissue organization rather than genetic mutations. In this paper, we study the argumentative strategy used by the advocates of TOFT to impose their view. In particular, we criticize their claim of incompatibility used to justify the necessity to definitively reject SMT. First, we note that since it is difficult to build a non-ambiguous experimental demonstration of the superiority of TOFT, its partisans add epistemological and metaphysical arguments to the debate. This argumentative strategy allows them to defend the necessity of a paradigm shift, with TOFT superseding SMT. To do so, they introduce a notion of incompatibility, which they actually use as the Kuhnian notion of incommensurability. To justify this so-called incompatibility between the two theories of cancer, they move the debate to a metaphysical ground by assimilating the controversy to a fundamental opposition between reductionism and organicism. We show here that this argumentative strategy is specious, because it does not demonstrate clearly that TOFT is an organicist theory. Since it shares with SMT its vocabulary, its ontology and its methodology, it appears that a claim of incompatibility based on this metaphysical plan is not fully justified in the present state of the debate. We conclude that it is more cogent to argue that the two theories are compatible, both biologically and metaphysically. We propose to consider that TOFT and SMT describe two distinct and compatible causal pathways to carcinogenesis. This view is coherent with the existence of integrative approaches, and suggests that they have a higher epistemic value than the two theories taken separately.

Anyway, keep an eye open for more on the tissue organization field theory — there seems to be a fair bit of ongoing debate in the scientific literature about it. I’ll keep telling everyone cancer is a developmental disease, so you need more developmental biologists to study it. Or, alternatively, every cancer biologist is already a developmental biologist.


Bedessem B, Ruphy S. (2015) SMT or TOFT? How the two main theories of carcinogenesis are made (artificially) incompatible. Acta Biotheor. 63(3):257-67.

Soto AM, Sonnenschein C (2011) The tissue organization field theory of cancer: a testable replacement for the somatic mutation theory. Bioessays. 33(5):332-40.

Conservative self-identifies with single-celled brainless organism

Among my usual flood of daily email, I frequently get tossed onto mailing lists for conservative think tanks. Why? I don’t know. I suspect that it’s for the same reason I also get a lot of gay porn in my email: not because I follow it or asked to be added, but because some tired d-bag with no imagination thinks its funny to dun me with more junk. The joke’s on them, though: I might keep it around and skim the stuff now and then to get inspiration for a blog post, and then click-click — a few presses of a button and I add the source to my junk mail filter, and never see it again.

No, I didn’t get inspired by gay porn today, but by drivel from some freakish conservative think tank called the Witherspoon Institute, about which I know next to nothing except that they’re another of those organizations that cloak themselves in the Holy Founding Fathers of America to promote illiberal non-freethinking anti-government BS. This latest is by a philosopher criticizing a book about modern reproductive biotechnologies. He doesn’t like ’em. Not one bit, no sir.

But you know an essay from a philosopher is going to be pretty much worthless when it opens and closes with references to… C.S. Lewis. I don’t know why that man gets so much happy clappy press from believers. I suspect he must have sold his soul to the devil.

Anyway, the bizarre part is in the middle, where Justin Barnard is poleaxed by the author’s, Steven Potter’s, willingness to destroy human embryos. Potter apparently considers several of the sides of the debate, but fails to come down on the side of the Religious Right, that is, that embryos are absolutely and undeniably full human beings from the instant of fertilization, instead espousing the dreadful notion that the definition of personhood falls into a huge gray area.

Potter’s own attempt to wrestle with the morality of destroying human embryos is philosophically, if not biologically, confused from the start. He begins by claiming that “each egg and sperm has the potential to make a person.” Biologically, this is simply false. Gametes, by themselves, have no intrinsic developmental potential for human personhood. Of course, Potter knows this. So his use of “potential” is likely more latitudinarian. Still, three pages later, Potter describes the zygote as having “remarkable potential.” “It can,” he explains, “turn itself into a person.” Ironically, Potter fails to recognize that this potentialist understanding of human personhood is at odds with his rather surprising admission of the embryological facts. Potter writes, “Of course we all began as a zygote. Everyone does.” What is shocking about this concession is what it so obviously entails–an entailment that seems lost on Potter. If I, the human being I am today, “began as a zygote,” then the zygote that began the-human-being-I-am-today was me–i.e., it was a human person. It was not merely a cell with “remarkable potential” to become me. It was me.

If anyone is confused here, it’s Barnard. Of course each egg and sperm has the potential to form a person, especially when we throw biotechnology into the equation, as the book he’s reviewing explicitly does. We already have techniques to revert and differentiate a sperm cell into an egg. For that matter, given time and research, we’ll be able to reprogram just about any cell into a totipotent state, and clone someone from a cheek swab. Does Mr Barnard regard every cell he sheds as a potential person?

Perhaps he wants to argue that a sperm or egg cell doesn’t have the potential for personhood without a human assist. But then by that limitation the zygote has to be excluded as well — no human zygote can develop to term without the extreme cooperation of another individual. Try it; extract a fertilized egg and set it in a beaker by your nightstand, and wait for a baby to crawl out. Won’t happen. A uterus and attendant physiological and behavioral meat construct, i.e., woman, is also an amazing piece of biotechnology that is a necessary component of the developmental process.

But the real blow to this whole “potential” argument is damaged irreparably by Barnard’s last few sentences — was he going for a reductio here? Is the entire essay an exercise in irony? ‘Cause that dope was dumb.

Yes, Mr Barnard began as a zygote. That does not mean the zygote was Mr Barnard. My car began as a stack of metal ingots and barrels of plastics; that does not imply that an ingot of iron is a car. My house began as a set of blueprints and an idea in an architect’s mind; nobody is going to pay the architect rent for living in his cranium or on a stack of paper in a cabinet. The zygote was not Justin Barnard, unless Justin Barnard is still a vegetating single-celled blob, in which case I’d like to know how he typed his essay.

Since Barnard claims to be a philosopher, I’ll cite another, a guy named Aristotle. This is a quote I use in the classroom when I try to explain to them how epigenesis works, in contrast to preformation. Aristotle did some basic poking around in chicken eggs and in semen, and he noticed something rather obvious—there were no bones in there, nor blood, nor anything meatlike or gristly or brainy. So he made the simple suggestion that they weren’t there.

Why not admit straight away that the semen…is such that out of it blood and flesh can be formed, instead of maintaining that semen is both blood and flesh?

Barnard is making the classic preformationist error of assuming that everything had to be there in the beginning: I am made of bones and blood and flesh and brains and guts and consciousness and self-identity, therefore the zygote must have contained bones and blood and flesh and brains and guts and consciousness and self-identity.

It didn’t.

Why not admit straight away that the zygote is such that out of it selfhood may arise, rather than maintaining that the zygote is the self?

In that case we have to recognize that the person is not present instantaneously at one discrete moment, but emerges gradually over months to years of time, that there were moments when self was not present and other moments when self clearly was present, and moments in between where there is ambiguity or partial identity or otherwise blurry gray boundaries. This is a conclusion that makes conservative ideologues wince and shy away — I think it’s too complicated for their brains, which may in some ways be equivalent to the gormless reflexive metabolic state of the zygote — but it is how science understands the process of development.

The new phrenology

Morphological variation is important, it’s interesting…and it’s also common. It’s one of my major scientific interests — I’m actually beginning a new research project this spring with a student and I doing some pilot experiments to evaluate variation in wild populations here in western Minnesota, so I’m even putting my research time where my mouth is in this case. There has been some wonderful prior work in this area: I’ll just mention a paper by Shubin, Wake, and Crawford from 1995 that examined limb skeletal morphology in a population of newts, and found notable variation in the wrist elements — only about 70% had the canonical organization of limb bones.

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I’ve also mentioned the fascinating variation in the morphology of the human aorta. Anatomy textbooks lay out the most common patterns, but anyone who has taught the subject knows that once you start dissecting, you always find surprises, and that’s OK: variation is the raw material of evolution, so it’s what we expect.

The interesting part is trying to figure out what causes these differences in populations. We can sort explanations into three major categories.

  1. Genetic variation. It may be the the reason different morphs are found is that they carry different alleles for traits that influence the developmental processes that build features of the organism. Consider family resemblances, for instance: your nose or chin might be a recognizable family trait that you’ve inherited from one of your parents, and may pass on to your children.

  2. Environmental variation. The specific pattern of expression of some features may be modified by environmental factors. In larval zebrafish, for instance, the final number of somites varies to a small degree, and can be biased by the temperature at which they are raised. They’re also susceptible to heat shock, which can generate segmentation abnormalities.

  3. Developmental noise. Sometimes, maybe often, the specific details of formation of a structure may not be precisely determined — they wobble a bit. The limb variation Shubin and others saw, for example, was almost entirely asymmetric, so it’s not likely to have been either genetic or environmental. They were just a consequence of common micro-accidents that almost certainly had no significant effect on limb function.

When I see variation, the first question that pops into my head is which of the above three categories it falls into. The second question is usually whether the variation does anything — while some may have consequences on physiology or movement or sexual attractiveness, for instance, others may really be entirely neutral, representing equivalent functional alternatives. Those are the interesting questions that begin inquiry; observing variation is just a starting point for asking good questions about causes and effects, if any.

I bring up this subject as a roundabout introduction to why I find myself extremely peeved by a recent bit of nonsense in the press: the claim that liberal and conservative brains have a different organization, with conservatives having larger amygdalas (“associated with anxiety and emotions”) and liberals having a larger anterior cingulate (“associated with courage and looking on the bright side of life”).

Gag.

I don’t deny the existence of anatomical variation in the brain — I expect it (see above). I don’t question the ability of the technique, using MRI, to measure the dimensions of internal structures. I even think these kinds of structural variations warrant more investigation — I think there are great opportunities for future research to use these tools to look for potential effects of these differences.

What offends me are a number of things. One is that the interesting questions are ignored. Is this variation genetic, environmental, or simply a product of slop in the system? Does it actually have behavioral consequences? The authors babble about some correlation with political preferences, but they have no theoretical basis for drawing that conclusion, and they can’t even address the direction of causality (which they assume is there) — does having a larger amygdala make you conservative, or does exercising conservative views enlarge the amygdala?

I really resent the foolish categorization of the functions of these brain regions. Courage is an awfully complex aspect of personality and emotion and cognition to simply assign to one part of the brain; I don’t even know how to define “courage” neurologically. Are we still playing the magical game of phrenology here? This is not how the brain works!

Furthermore, they’re picking on a complex phenomenon and making it binary. Aren’t there more than one way each to be a conservative or a liberal? Aren’t these complicated human beings who vary in an incredibly large number of dimensions, too many to be simply lumped into one of two types on the basis of a simple survey?

This is bad science in a number of other ways. It was done at the request of a British radio channel; they essentially wanted some easily digestible fluff for their audience. The investigator, Geraint Rees, has published quite a few papers in credible journals — is this really the kind of dubious pop-culture crap he wants to be known for? The data is also feeble, based on scans of two politicians, followed by digging through scans and questionnaires filled out by 90 students. This is blatant statistical fishing, dredging a complex data set for correlations after the fact. I really, really, really detest studies like that.

And here’s a remarkable thing: I haven’t seen the actual data yet. I don’t know how much variation there is, or how weak or strong their correlations are. It’s because I can’t. This work was done as a radio stunt, is now being touted in various other media, and the paper hasn’t been published yet. It’ll be out sometime this year, in an unnamed journal.

We were just discussing the so-called “decline effect”, to which my answer was that science is hard, it takes rigor and discipline to overcome errors in analysis and interpretation, and sometimes marginal effects take a great deal of time to be resolved one way or the other…and in particular, sometimes these marginal results get over-inflated into undeserved significance, and it takes years to clear up the record.

This study is a perfect example of the kind of inept methodology and lazy fishing for data instead of information that is the root of the real problem. Science is fine, but sometimes gets obscured by the kind of noise this paper is promoting.

I have to acknowledge that I ran across this tripe via Blue Girl, who dismisses it as “sweeping proclamations about the neurophysiological superiority of the liberal brain”, and Amanda Marcotte, who rejects it because “This kind of thing is inexcusable, both from a fact-based perspective and because the implication is that people who are conservative can’t help themselves.” Exactly right. This kind of story is complete crap from the premise to the data to the interpretations.