Front-loading Hedgehog

The hypothesis of front-loading continues to gather traction.  Consider this description of the Hedgehog signaling pathway:

In a growing embryo, cells develop differently in the head or tail end of the embryo, the left or right, and other positions. They also form segments which develop into different body parts. The hedgehog signaling pathway gives cells this information that they need to make the embryo develop properly. Different parts of the embryo have different concentrations of hedgehog signaling proteins. The pathway also has roles in the adult. When the pathway malfunctions, it can result in diseases like basal cell carcinoma. [1]

The hedgehog signaling pathway is one of the key regulators of animal development conserved from flies to humans. The pathway takes its name from its polypeptide ligand, an intercellular signaling molecule called Hedgehog (Hh) found in fruit flies of the genus Drosophila. Hh is one of Drosophila’s segment polarity gene products, involved in establishing the basis of the fly body plan. The molecule remains important during later stages of embryogenesis and metamorphosis.

So here we have a circuit that is essential to the development of metazoan body plans.  How in the world could we front-load this information into a single-celled organism?

Back in January 2009, Techne showed that many of the components of this circuit effectively existed long before the circuit was deployed:

Therefore, words like “pre-existing”, “latent” and “potential” seem apt in describing the hedghog signaling pathway and the unfolding of multicellular body plans in relation to the increase in atmospheric oxygen pressure.

Well, a recent paper came out in June that helps to extend and expand on this line of thinking.  Let me quote a couple of juicy excerpts:

Complex body plans require sophisticated cell–cell signaling pathways. How these pathways evolved is often not very well understood. Here, we argue that the Hedgehog (Hh) signaling pathway may have arisen from systems that were originally designed for the transport and homeostasis of certain bacterial sterol analogs—the hopanoids.

We assume that the original function of Ptc was simply to transport an unwanted lipid molecule out of the cell. Smo, on the other hand, derives from a protein family whose main function is to sense and to transduce extracellular signals (i.e., the GPCR family). Therefore, we propose the following scenario: let us imagine that, in primitive eukaryotes, Smo was initially a receptor sensing lipid molecules and was acting upstream of the primitive Ptc transporter (Figure 3). The two molecules would have formed a simple homeostasis system; Smo would sense the abundance of a certain lipid and would transcriptionally induce Ptc whenever this lipid was in excess and needed to be removed from the membrane (i.e., pumped away). We propose that when multicellular organisms arose, this system was available and was recruited for a new purpose: cell-to-cell signaling.

The intriguing homology between components of lipid homeostasis pathways and components of the Hh signaling pathway leads to the hypothesis that the central membrane–players of the Hh signaling cascade—Smo and Ptc—evolved from a pre-existing lipid-sensing/homeostasis pathway. We propose a model of simple evolutionary steps, which posits that Ptc acts by pumping an activator of Smo, rather than an inhibitor. This scenario is compatible with most experimental data so far. The step-wise construction of pathways from older, pre-existing modules is turning out to be a general theme in developmental biology [24].

This general theme of developmental biology is precisely what we would expect from front-loading and this particular example is most delicious.

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5 responses to “Front-loading Hedgehog

  1. evolvingideas

    Yes, but it is also precisely what you would expect from a process without front-loading, since all our present systems must have evolved from preexisting systems with other functions.

    You need to find proof and not just a lot of instances of biology that could possibly be explained by your theory.

    For example, to illustrate the pinciple, you could try one of those experiments where bacteria are allowed to evolve over very many generations, and you could predict from your front-loading hypothesis which changes will take place, and then see if they do.

  2. Hi evolving ideas,

    I’m not just finding instances that “could possibly be explained” by the hypothesis of front-loading. I’m finding an array of instances that are precisely what I would expect from a front-loading process.

    As for finding proof, I’m going to write up a blog entry that focuses on the central metaphor of my approach. It’s crucial to understanding my position.

    For now, let’s consider your point about non-teleological evolution – “all our present systems must have evolved from preexisting systems with other functions.”

    If true, this immediately focuses our attention on the original preexisting systems. Does this mean every protein is homologous to each other, given that every protein ultimately descended from the same original self-replicating RNA molecule?

    I think not. In fact, it is simply not true all our present systems must have evolved from preexisting systems with other functions. From a non-telic perspective, a very simple system could have been cobbled together by using some parts which arose de novo. That is, some parts could have evolved from preexisting DNA sequence that had no function. After all, when using a random search, the chances of finding an 80 amino acid chain that yielded an activity are 1 in 10^12. Since there are over 10^30 bacteria alone on this planet, why think evolution must borrow from a pre-existing system/function?

    Using the example above, what if it was determined that Ptc had no functional precursor? At that point, you would have two choices. You could cite this as a gap and insert creationism as the cause. Or, you could argue that Ptc arose de novo from preexisting nucleotide fragments.

    I’m simply focused on the fact that the authors of this paper “propose that when multicellular organisms arose, this system was available and was recruited for a new purpose: cell-to-cell signaling.” In other words, a preadaptation and predisposition was in play. I’m focused on the plausibility of front-loading and not its proof.

    Which takes us to you last comment:

    “For example, to illustrate the pinciple, you could try one of those experiments where bacteria are allowed to evolve over very many generations, and you could predict from your front-loading hypothesis which changes will take place, and then see if they do.”

    For the sake of argument, let’s think of front-loading as a “program.” What I am doing is gathering clues that point to the existence of a “program.” That is a far cry from understanding how the program works (analogous to the mainstream distinction between the fact of evolution as a historical process and the mechanisms of evolution still being elucidated). To make such an experimental prediction, one would need to have solid knowledge of how front-loading works/worked. And I’m afraid I don’t have a good grasp, beyond the broad brush strokes, as to how front-loading occurred (and it’s not as if there is a community of experts I can consult). Of course, this may change some time in the future, where some concept crystallizes with enough clarity to generate a distinctive, testable hypothesis for such an experiment. And if that happens, at that point we can refer to front-loading as science.

    But there is a catch. Suppose I write a grant, get funding, and after several years, do exactly as you say. Why wouldn’t the reaction/response be as follows?

    Yes, but it is also precisely what you would expect from a process without front-loading.

  3. evolvingideas

    Hi Michael!

    Yes, I agree completely that new proteins may arise de novo and not just by modifications of preexisting ones. I was generalising a bit too far in my previous comment .

    The more important point is the second. You do not set out, if I understand you correctly, to prove front-loading at this point. Instead, you gather examples that could plausibly be explained by front-loading.

    Regardless of these examples, I do not find front-loading plausible because it presupposes a “designer”, a very unlikely entity.

    Therefore, in order to make this hypothesis interesting, you need to put it to a real test. As you write, this is very difficult. What I wanted to suggest was how it could be done in principle.

    Why would the response not be “Yes, but it is also precisely what you would expect from a process without front-loading”?

    Because evolution could go very many ways if it were left to chance and selection pressures. If you try to do a proper Popperian hypothesis testing, you would make a prediction about which way it will go, and then attempt to disprove it by running the experiment. If you could accurately predict evolutionary change, then you would have a strong foundation.

    It seems that we are in agreement – front-loading is not science at this point but nothing prevents it, in principle, from becoming science. But the practical obstacles are pretty big.

  4. Hi evolvingideas,

    You write:

    “You do not set out, if I understand you correctly, to prove front-loading at this point. Instead, you gather examples that could plausibly be explained by front-loading.
    Regardless of these examples, I do not find front-loading plausible because it presupposes a “designer”, a very unlikely entity.”

    I’m not sure how anyone can determine whether or not a designer is or is not a “very unlikely entity,” but I do acknowledge your concern as legitimate. Since front-loading does indeed presuppose a “designer,” this will be the sticking point for most. Unfortunately, the truth of front-loading does not entail our ability to uncover some independent evidence for the existence of the designer.

    At this point, I would simply note two things.
    First, I would not expect you to acknowledge that front-loading is plausible since I have no independent evidence of any designer for life. Second, I would note that you have not provided any reason for me to think that front-loading is implausible. Thus, hopefully you can at least understand why I continue to explore this issue as a deepening intellectual curiosity.

    Let me mention one more thing. In the blog entry, the researchers are quoted:

    The step-wise construction of pathways from older, pre-existing modules is turning out to be a general theme in developmental biology [24].

    Indeed. But let’s not quickly forget that while the hypothesis of front-loading predicts such deep homology, the non-teleological perspective really does not. We can now see this from two vantage points:

    1. As a matter of historical record, scientists did not expect to find such deep homology. On the contrary, they were shocked and surprised. I documented this in an earlier blog entry.

    2. Since proteins and genes can arise de novo, then a non-telic perspective would need extraneous reasons for predicting ancient homologies. As it stands, the non-telic perspective simply accounts for either finding, after the fact.

    It seems that we are in agreement – front-loading is not science at this point but nothing prevents it, in principle, from becoming science. But the practical obstacles are pretty big.

    Yes, we agree front-loading is not science. Where we disagree is the belief that “nothing prevents it, in principle, from becoming science.” What prevents it from becoming science is that it is deeply teleological. If “detecting design” is akin to detecting another mind, then it is too subjective to ever become science.

    I probably confused this point when writing above, “And if that happens, at that point we can refer to front-loading as science.” But that was sloppy on my part. What would become science at that point is the ability of the human researcher to predict some aspect of evolutionary change. No one would consider this scientific evidence for front-loading, just as artificial selection is not considered evidence for a non-human, artificial selector.

    Front-loading, because of its teleological nature, will always remain outside of science (as is the case with many other areas of human inquiry). But it can be used to derive subsidiary hypotheses that can be tested in science. That is, it is a hypothesis that is responsive to what science finds and can also have input into what science finds.

    Anyway, I really enjoy your comments!

  5. Pingback: Mechanisms of Biological Intelligent Design « The Genome's Tale

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