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.

Cincinnati, 16 June…whatcha doin’?

A student and I are going to attend the 2017 Midwest Zebrafish Meeting in Cincinnati, Ohio. We’re getting in on Thursday night, and the meeting schedule has us free all day Friday, until the opening remarks at 6pm.

Hmmm. What to do all day long? What embarrassing, horrible spectacle is there within a short drive of Cincinnati that could provide amusement?

You guessed it. I’m going to the Ark Encounter! I imagine there will be lots of developmental biologists and geneticists in town that day…anyone want to join us? Or if you’re not there for the meeting, but just idling about in the neighborhood, feel free to come along, too. It’s not as if you need a Ph.D. to laugh at the pseudoscience on display.

Also, if anyone wants to meet up for serious conversation during the conference, I’m up for that — as mentioned above, I’ll be there with a student who might be looking for a graduate program in another year, and I’d like to introduce them around.

Fun with the nasal cycle

Did you know that most of us have two nostrils? It’s strange — we have a single trachea, but it branches into two pathways up top, and furthermore, those two terminal pathways are elaborate and mazelike, with a network of sinuses and these convoluted turbinate bones taking up much of the space behind your nose. I’d always just chalked it up to a side effect of bilateral symmetry (eh, you know, developmental biologist), but at the very least, it does have physiological consequences. Among those consequences is that there is a nasal cycle. You don’t breathe in equally through both nostrils, there is an alternating rhythm.

Try it yourself right now. Consciously consider what you feel as you breathe in and out normally — you probably can detect that one nostril seems a little bit more open than the other (if you’ve got a cold or allergies, your perception of this phenomenon may be messed up. Sorry. Get better soon.) As I sit here, for instance, I can tell that my right nostril has somewhat freer airflow than my left. It’s not that I’m having any problems breathing through either, it’s a subtle difference, simply a small, barely detectable asymmetry that is unnoticeable except when I’m consciously thinking about my breathing.

MRI scans through a face

The cool thing about it, though, is that it alternates with a cycle length between about half an hour and 8 hours. The mechanism for that is that a portion of your septum and your inferior turbinate are covered with erectile tissue that becomes gradually engorged in response to sustained airflow, and relaxes as airflow is reduced, so your nostrils take turns getting aroused by breathing and then swapping off with each other to relax and recover.

You can measure the nasal cycle in a precise and continuous way with scientific instruments, if you’d like, but there’s also a rough and ready way. This weekend my wife and I drove to a meeting in Glenwood, and then on to Minneapolis, so we had a couple of long drives together, and we were talking about respiratory physiology, as one does, when I explained about this nasal cycle thing, and we decided to measure it. Since we didn’t have access to an electronics lab in the car, we did a subjective estimate: every half hour, we’d just try to be consciously aware of our breathing and report which nostril was doing most of the work. It beats playing Slug Bug, anyway.

So we did a day’s worth of crude measurements. One problem right away was that Mary was a bit congested and stuffed up, which meant the whole day went by with no change for her, which was a bit boring. She did finally detect a shift that evening, so her nasal cycle was estimated to be a bit longer than 8 hours. Another slight problem is that we also took our son and his girlfriend out to lunch, and mid-meal we had to announce “Nostril check!”, which meant we got some funny looks. But that’s OK, I’m used to getting funny looks.

As for me, I’ve gotten over a nasty cold that had been afflicting me for a while, so my face and sinuses and nasal erectile tissue were in fine fettle, and I was able to measure a couple of cycles, which were both about 3 hours in length.

Give it a try yourself. The obvious weaknesses with the way we were doing it is that the observations are personal and subjective, unlike those done with gadgetry that directly measures airflow, and since we were only doing a check every half hour our results were pretty chunky. The interesting thing about it, though, is that this is a rhythm our bodies express throughout your life, and most of us never even notice. It makes one wonder what other sneaky little patterns your organs are doing without your permission or control.

Kahana-Zweig R, Geva-Sagiv M, Weissbrod A, Secundo L, Soroker N, Sobel N. (2016) Measuring and Characterizing the Human Nasal Cycle. PLoS One 11(10):e0162918

Clearly, humans are born with a natural love of cephalopods

Forget teddy bears — we’ve been representing the wrong species in our children’s toys. A hospital in Scotland has found that their premature babies like crocheted octopus toys — there’s even a group dedicated to providing them.

So, why octopuses? Well, apparently, the tentacles remind the baby of clinging to the umbilical cord in the womb, and this makes them feel safe and secure.

The hospital cares for approximately 1,000 premature babies every year, so that requires lots of octopuses for cuddling. Having the octopus close to hand can also prevent the babies from trying to pull out their tubes.

It’s not just humans, either. Our cat has a favorite toy, a crocheted octopus, of course, which she’ll drag around while making strange noises. There’s just something cute and adorable about octopuses.

Aaargh. It’s like watching the spread of a plague.

More noise from that perfectly respectable cephalopod RNA editing paper with the bad press release. This time it comes from Quartz.

It turns out these impressive abilities may originate at the molecular level. Researchers from Tel Aviv University in Israel and the Marine Biological Laboratory at Woods Hole, Massachusetts, published a paper on April 6 illustrating that octopuses and their relatives, squid and cuttlefish, can readily change the way they use their DNA. Rather than using their genetic code as a blueprint to build the proteins they need to survive, cephalopods use it more like guidelines.

“This may explain why they’re such good problem solvers,” Clifton Ragsdale, a neurobiologist at the University of Chicago unaffiliated with the paper, told Scientific American.

NO IT DOESN’T! If a paper came out that announced that neurons get more of their ATP from glycolysis (which is actually often the case), would you then declare that you’ve figured out how humans got to be so smart? No, you wouldn’t, because the mechanism is so far from the outcome. LeBron James likes Fruity Pebbles, that must be the secret of his basketball skills!

RNA editing is a mechanism that allows the proteins produced by genes (and also, and probably to a greater extent, the non-coding RNAs) to acquire different sequences over time, just like mutations to the nucleotide sequence would. It tells you nothing about the complex sequence of historical events that led to the emergence of greater intelligence.

Also, “Rather than using their genetic code as a blueprint to build the proteins they need to survive, cephalopods use it more like guidelines” is just wrong and implies so much nonsense. Who or what is following these “guidelines”? They make it sound like squid take their genetic output and consciously adjust it to suit some vaguely understood better goal. Post-transcriptional processing is chemistry, too!

I’m also chattering away to a tiny audience over on Mastodon (I’m @pzmyers@octodon.social, if you’re interested), so I figure I’ll also put my comments there over here, so you can argue with me.

It’s annoying because the study doesn’t address the question everyone thinks it does. It’s clear that most people are reading the press release, not the paper, and can’t understand the science behind it.

It’s a bad translation problem.

So now I’m wondering about #scicomm responsibilities. SJ Gould & Dawkins made masterful contributions to the public understanding of science, but they also separated everyone from the source material for their ideas, to the point everyone credits them completely for their evolutionary views.

You have to get down to the root to see the problems. Great communicators seem at their best explaining the twigs and leaves.

The worst take on that cephalopod RNA editing story yet

That article I wrote up today? Take a look at the colossal botch phys.org made of it.

How octopuses, squid, and cuttlefish defy genetics’ ‘central dogma’

Jesus fuck, how can you write for a science news site and get everything that wrong? The central dogma of molecular biology (not genetics, dinglepoofs) says that the information in proteins can’t be written back into DNA. This study doesn’t even try to address the central dogma, much less “defy” it.

Now look at this paragraph. There’s a misplaced quotation mark in there, so I’m not even sure what part is actually the words of the biologist. No, not all information is stored in DNA. The RNA editing part is not new, not surprising, and isn’t going to surprise any knowledgable biologist (the degree that some cephalopods exploit RNA is unusual, but it’s not in itself revolutionary), and most definitely does not invalidate Crick’s central dogma.

In fact, RNA editing is so rare that it’s not considered part of genetics’ “Central Dogma.” “Ever since Watson and Crick figured out that genetic information is stored in DNA, we’ve had this view that all the information is stored in DNA, and it’s faithfully copied to another molecule when it’s used—that’s RNA, and from there, it’s translated into the proteins that do all the work. “And it’s generally assumed that that’s a pretty faithful process,” explains study co-author Joshua Rosenthal, a cephalopod neurobiologist at the Marine Biological Laboratory in Woods Hole, MA. “What the squid RNA is showing is that that’s not always the case—that, in fact, organisms have developed a potent means to manipulate information in RNA.”

I’m not even going to begin on all the news stories crediting cephalopod intelligence to this process.