Evolution of blood clotting

A link to material that didn't make it into Finding Darwin's God.

Michael Behe is in awe of the the intricate complexity of this system, and so am I. And he is also correct in pointing out that if we take away part of this system, we're in trouble. Hemophiliacs, for example, are unable to synthesize the active form of Factor VIII. This means that they are unable to complete the final step of one of the pathways, and that's why hemophilia is sometimes known as the bleeder's disease. Defects or deficiencies in any of the other factors are equally serious. No doubt about it - clotting is an essential function and it's not something to be messed with. But does this also mean that it could not have evolved? Not at all. The key to understanding the evolution of this intricate system, as Russell Doolittle has pointed out, is the fact that the clotting factors share an exquisite and revealing similarity.

Building the Machine

To paraphrase Darwin, the notion that evolution could have produced a system as intricate as the blood clotting cascade seems, we might freely confess, "absurd in the highest possible degree." This is especially true if you believe, as Behe seems to, that clotting is not possible until the entire cascade of factors is assembled.

But we already know that evolution doesn't start from scratch, and it doesn't need fully-assembled systems to work. Remember the lobster system as an example. Blood clotting evolved there from two pre-existing proteins, normally found in separate compartments of the body, that had a fortuituous interaction when damage to a blood vessel brought them together. Once that interaction was established, natural selection did the rest.

Could something like this have happened here?

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Next, if the clotting cascade really evolved the way I have suggested, the the clotting enzymes would have to be near-duplicates of a pancreatic enzyme and of each other. As it turns out, they are. Not only is thrombin homologous to trypsin, a pancreatic serine protease, but the 5 clotting proteases (prothrombin and Factors X, IX, XI, and VII) share extensive homology as well. This is consistent, of course, with the notion that they were formed by gene duplication, just as suggested. But there is more to it than that. We could take one organism, humans for example, and construct a branching "tree" based on the relative degrees of similarity and difference between each of the five clotting proteases. Now, if the gene duplications that produced the clotting cascade occurred long ago in an ancestral vertebrate, we should be able to take any other vertebrate and construct a similar tree in which the relationships between the five clotting proteases match the relationships between the human proteases. This is a powerful test for our little scheme because it requires that sequences still undiscovered should match a particular pattern. And, as anyone knows who has followed the work in Doolittle's lab over the years, it is also a test that evolution passes in one organism after another.

There are many other tests and predictions that can be imposed on the scheme as well, but one of the boldest was made by Doolittle himself more than a decade ago. If the modern fibrinogen gene really was recruited from a duplicated ancestral gene, one that had nothing to do with blood clotting, then we ought to be able to find a fibrinogen-like gene in an animal that does not possess the vertebrate clotting pathway. In other words, we ought to be able to find a non-clotting fibrinogen protein in an invertebrate. That's a mighty bold prediction, because if it could not be found, it would cast Doolittle's whole evolutionary scheme into doubt.

Not to worry. In 1990, Xun Yu and Doolittle won their own bet, finding a fibrinogen-like sequence in the sea cucumber, an echinoderm. The vertebrate fibrinogen gene, just like genes for the other proteins of the clotting sequence, was formed by the duplication and modification of pre-existing genes.

Now, it would not be fair, just because we have presented a realistic evolutionary scheme, supported by gene sequences from modern organisms, to suggest that we now know exactly how the clotting system has evolved. That would be making far too much of our limited ability to reconstruct the details of the past. But nonetheless, there is little doubt that we do know enough to develop a plausible and scientifically valid scenario for how it might have evolved. And that scenario makes specific predictions that can be tested and verified against the evidence.