For some unknown reason, many critics of ID think that design = uniqueness. That is, if a biological feature X is similar to biological feature Y, we are supposed to rule out design and instead infer common ancestry. But are things really this simple?

Consider tubulin and ftsZ. The former is a very important eukaryotic cytoskeletal protein involved in maintaining the cell structure, coordinating intracellular movement, separating chromosomes during mitosis, and forming the backbone of the eukaryotic flagellum. The latter gene product is a bacterial protein that plays an essential role in splitting the two cells during cell division and may also have cytoskeletal roles.

Although the two proteins have a similar role, most scientists did not originally consider them homologous (related by a common ancestral sequence). In a paper published in Cell by David Edgell and W. Ford Doolittle back in 1997, they noted that sequence identity less than 20% is attributed to chance. They also argued a "common function alone is not sufficient evidence of homology because two proteins can convergently arrive at the same mechanistic, structural, or biochemical solution to a particular biological problem." In fact, speaking directly about tubulin and ftsZ, they wrote, "amino acid alignments between these two proteins are not very convincing."

But today, the situation has changed as most scientists now think the two proteins are homologous. Why? The 3-D structure of both proteins has been solved and have been found to be very similar. One scientist has recently explained the picture:

 There is now overwhelming evidence in favor of the idea that FtsZ is a homolog of tubulin, the ubiquitous eukaryotic cytoskeletal protein involved in many essential cellular processes including mitosis. Despite only limited primary sequence homology centered around a GTP binding motif termed the `tubulin signature sequence', the recently solved crystal structures of FtsZ and tubulin show extensive structural homology throughout the proteins. In addition, FtsZ, like tubulin, binds and hydrolyzes GTP and assembles into protofilaments that have structures similar to those within microtubules. This assembly is GTP-dependent and disassembly occurs when the GTP is exhausted, suggesting that FtsZ polymers, like microtubules, are dynamically unstable. FtsZ and tubulin also share similar responses to hydrophobic dyes: while bis-anilino-naphthalenesulfonate (bis-ANS) inhibits polymerization of both proteins, the related dye ANS has no effect on either. Another link between FtsZ and tubulin in vivo is that they can be made to coalign as polymers in mammalian cells in the presence of vinblastine, a microtubule-destabilizing drug. - Margolin, W. Themes and variations in prokaryotic cell division. Fems Microbiology Reviews, 2000 Oct, 24(4):531-48.

While this view is quite reasonable in science, we must remember that science is looking for the best non-teleological explanation. Thus, although no calculations have been made, it seems intuitively implausible that such similarities could be due to chance. And in science, chance is the only other viable alternative explanation to common descent.

But if we step out of this box and entertain teleological causes, structural similarity, and the similar properties that follow, are insufficient reason to infer common descent in place of design. In other words, while I would agree that both sequence and structural similarity are good evidence for common descent, this only holds true as long as we have no reason to suspect ID may be lurking in the background.

Now, my working hypothesis entails that life appeared on this planet as a consequence of seeding and the life forms that were seeded represented a consortium of sophisticated cell types. Since tubulin is basic to eukarya and ftsZ is basic to bacteria, and since both eukarya and bacteria may have been among that consortium (or separated by two distinct seeding events), ID may be lurking in the background. So let's see how we can think about the two proteins from an ID perspective.

If these two proteins arose from a common ancestor, then what is being conserved is the structure. But structure in this case is not a simple story, at least for tubulin. Neither alpha nor beta tubulin will spontaneously fold into the proper conformation in vitro . In fact, the folding pathways of both proteins are not only distinct, but quite complex. Here's a brief breakdown.

First, during and right after translation, the tubulin nascent chains are probably bound to chaperone called a pre-foldin. This shuttles the amino acid chains to the eukaryotic chaperonin (CCT). There, it is partially folded. After release from the chaperonin complex, alpha- and beta-tubulins are captured by cofactors B and A, respectively, which subsequently are replaced by cofactors E and D. Then, the two pathways (alpha-tubulin-cofactor E and beta-tubulin-cofactor D) converge, forming a complex consisting of all four molecules. Finally, cofactor C joins and, upon GTP hydrolysis, assembly-competent alpha/beta-tubulin heterodimers are released. Cofactors D and E are indispensable and play parallel roles in the folding reactions of beta- and alpha-tubulin, respectively.

The interesting thing then is the structure of tubulin is not merely a function of amino acid sequence, but also is dependent on a whole set of eukaryal chaperones. And what is even more interesting is that it is not clear that the bacterial chaperonin, GroEL, can substitute for CCT. For example, it is know that GroEL cannot fold actin (the other major eukaryal cytoskeletal protein). Does anyone know if ftsZ can fold by itself in vitro ? If not, it would still seem it doesn't need extensive help as does tubulin, as ftsZ is present in Mycoplasma, yet these bacteria seem to possess only the minimal complement of bacterial chaperones (the dnaK system and the GroEL chaperonin).

In the end, a non-teleologist is nevertheless expected to infer homology at this point (for lack of anything better), although we might have expected actin and ftsZ to be better candidates for homology given their closer functional similarities (like ftsZ, actin forms rings around the cell to partition it during cell division). Nevertheless, I think this is fertile ground for a teleological approach.

If we entertain teleological explanations, there is nothing that compels us to move beyond a form/function similarity. But an ID theorist can take it further than this and ask why such similar structures would be employed differently? There should be good design reasons for employing essentially the same structure differently. First, what is the functional similarity? Apparently, to bind and hydrolyzes GTP such that assembly into protofilaments occur that tap into the design principle of dynamic instability (where GTP binding and hydrolysis functions as a switching mechanism). Let's call this the GTPase-dependent Protofilament Design (GPD) and we can think of it as a framework. But this framework/function, by itself, is biologically useless. In fact, unless it is tied to a biological function, it works merely as an wasteful energy sink (a futile GTPase cycle). Of course, for the biological function we need a biological context. This context then works to specify how one decorates the framework to tap into GPD's functional potential. In this case, we have the distinct bacterial and eukaryal contexts that differ in many significant ways. In a eukaryote, GPD is built upon to become tubulin, whereby it will play an important scaffold function in accord with the tensigrity model. What's more, it will serve as tracks for eukayal motor proteins, kinesin and dynein. It will also be called upon to form motility structures (flagella) and to play an essential role in segregating newly formed genetic material. In bacteria, GPD is built upon differently to serve the bacterial context. Here, it will play an important role in cytokinesis and thus interact with a different set of players. It is probably also associated with a bacterial cytoskeleton which may play more of a organizational role than a true skeletal role (the latter role is largely fulfilled by the cell wall). [1] The point is that a similar framework may have simply been exploited by a designer in different contexts (as a crude analogy, I look at my fan blowing air on me this hot night and am reminded that in another context, a very similar structure is used to move boats about). This ID hypothesis predicts several things.

First, we would predict that despite their very similar conformations and functional framework, ftsZ and tubulin can not substitute for each other since the two proteins are more than their shared framework. And this is what we see.

Secondly, we can predict there are fundamental differences reflecting the fact that the two are more than their shared framework (as is the case with my fan and a boat propeller). Some evidence along these lines is already coming out:

FtsZ is a bacterial homolog of tubulin that is essential for prokaryotic cytokinesis. In vitro, GTP induces FtsZ to assemble into straight, 5-nm-wide polymers. Here we show that the polymerization of these FtsZ filaments most closely resembles noncooperative (or "isodesmic") assembly; the polymers are single-stranded and assemble with no evidence of a nucleation phase and without a critical concentration. We have developed a model for the isodesmic polymerization that includes GTP hydrolysis in the scheme. The model can account for the lengths of the FtsZ polymers and their maximum steady state nucleotide hydrolysis rates. It predicts that unlike microtubules, FtsZ protofilaments consist of GTP-bound FtsZ subunits that hydrolyze their nucleotide only slowly and are connected by high affinity longitudinal bonds with a nanomolar K(D).

and

Tubulin and FtsZ share a common fold of two domains connected by a central helix. Structure-based sequence alignment shows that common residues localize in the nucleotide-binding site and a region that interacts with the nucleotide of the next tubulin subunit in the protofilament, suggesting that tubulin and FtsZ use similar contacts to form filaments. Surfaces that would make lateral interactions between protofilaments or interact with motor proteins are, however, different.

Thirdly, we might expect these differences to be very important, explaining why a designer would employ the different variations on the GPD theme. And one of the facts not mention thus far in this thread is that although both ftsZ and tubulin have very different amino acid sequences when compared to each other, the sequences of both ftsZ and tubulin are highly conserved in bacteria and eukarya, respectively. In other words, when we compare ftsZ sequence within bacteria and tubulin sequence with eukarya, we find strong sequence conservation. FtsZ, for example, shows 40-50% identity when very different forms of bacteria are compared and I believe the tubulin conservation is even higher. In fact, one paper on my desk states "tubulins are among the most conserved proteins known."

This pattern is consistent with independent origins by design. That is, the first bacteria were endowed with a GPD variant known as ftsZ that has been conserved for billions of years due to its important design objective. Similarly, the first eukaryotes were endowed with a GPD variant known as tubulin that has been conserved for billions of years due to its important design objectives.

On the other hand, if we try to force common descent on the two distinct, highly conserved proteins, we face a strange situation. For prior to the evolution of ftsZ and tubulin from this hypothetical ftsZ/tubulin-like precursor, there was no apparent functional constraint. If there was, it is difficult to explain how the two sequences so radically drifted from each other only to be locked into place (of all places) in the last common ancestors of eukaryotes and bacteria. But wait a minute. The 3-D structure was being conserved. That's the basis for inferring the common descent. Yet what was it doing prior to the two sequences getting locked into place? Nothing bacterial. Nothing eukaryotic.

Fourth, we would predict that this basic principle of design, where a core framework is built and then the design potential is fleshed out, might be uncovered in our own process of designing proteins. In this regard, a recent review on rational protein design by one scientist (Hellinga, H. W. (1997). Rational protein design: Combining theory and experiment. Proc. Natl. Acad. Sci. U. S. A. 94: 10015-10017 ) is informative:

At the center of the design approach is the "design cycle," in which theory and experiment alternate. The starting point is the development of a molecular model, based on rules of protein structure and function, combined with an algorithm for applying these. This is followed by experimental construction and analysis of the properties of the designed protein. If the experimental outcome is failure or partial success, then a next iteration of the design cycle is started in which additional complexity is introduced, rules and parameters are refined, or the algorithms for applying them are modified.

Why is this relevant? Consider the following:

All design methods use the same general approach to reduce the immense complexity of the search problem. The structure of a protein backbone is chosen a priori, kept fixed, and redecorated with different amino acid sequences that are predicted to be structurally compatible with that fold. This "inverse folding" approach therefore removes the backbone conformational degrees of freedom from the design problem.

The first rational design approaches used qualitative rules of protein structure applied by inspection. These experiments established that it is possible to create sequences de novo that adopt defined structures. Furthermore, they demonstrated that, by following a progressive design strategy [or "hierachic design"] in which increasing levels of complexity are iteratively introduced, new insights into the fundamentals of protein structure and function can be gained. One of the remarkable observations of these experiments was that it is surprisingly easy to obtain globally correct folds.

Here we can see that the procedure of our own rational protein design starts with choosing a particular structure (protein backbone) and then decorates it with different amino acids to see how well they work. This is similar to the hypothetical GPD approach I described above. The difference is that we are still learning to design proteins and typically have one end-point in mind when doing so. Intelligent beings with much more experience at this might be able to take this approach further. That is, with an extensive history of the "design cycle" under the belt, in which theory and experiment alternated, designers may have stumbled upon many interesting protein features that could be exploited in different contexts. Furthermore, with a sufficient knowledge base, one could specifically explore the "functional space" inherent in any particular structure through this design cycle. But perhaps the most significant point is this: proteins with similar conformations, but differing properties, are expected to be found through a process of rational protein design. Thus, ID is a known mechanism that could very well generate the type of similarities seen in ftsZ and tubulin and is not an ad hoc consideration.

Finally, it is not known if the sequence seen in ftsZ can be bridged to tubulin by walking through step-by-step changes, under the constraint of the genetic code, such that the basic 3-D shape would be retained. Since selection has maintained this shape, if no such pathway exists, common descent fails as the explanation.

The bottom line is that while non-teleologists will of course interpret similarities to mean common descent, a teleologist is free to consider other possible causal explanations. There is no compelling reason to attribute a similar framework to common descent, indicating once more just how ambiguous this all can be.

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[1] I have long used ID to predict that the bacterial cytoplasm will not be a soup.

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