Evolution of blood clotting mechanism

  • Thread starter Defennder
  • Start date
  • #1
Defennder
Homework Helper
2,591
5

Main Question or Discussion Point

I'm currently reading this article by Ken Miller on a plausible account of how the blood clotting mechanism in vertebrates might have evolved. There's some things I don't understand but which I hope someone here will explain to me:

Here's the article:

http://www.millerandlevine.com/km/evol/DI/clot/Clotting.html

All quotes are from the hyperlinked article.

However, the original gene had a control region that switched it on only in the pancreas. During the duplication, the control region of the duplicate is damaged so that the new gene is switched on in both the pancreas and the liver. As a result, the inactive form of the enzyme, a zymogen, is relesased into the bloodstream.
What does it mean for the gene to be "switched on" only in the pancreas? And more importantly, why does the fact that it being switched on in both the pancreas and liver causes the enzyme to be released into the bloodstream?

Most serine proteases, including trypsin and thrombin, are auto-catalytic. That means that some extent they can activate themselves, in many cases by cleaving a few amino acids to switch on their active sites.
If serine proteases are, as the article states able to self-activate (by mere presence of amino acids in the bloodstream), and if, by the first quoted paragraph, where the serine protease is released into the bloodstream, then wouldn't it be possible for blood to clot itself even when no blood vessels are broken? If so, wouldn't this be disruptive to normal functioning?
 

Answers and Replies

  • #2
Gokul43201
Staff Emeritus
Science Advisor
Gold Member
7,051
17
Experiments have shown that genes randomly switch between an activated state (on) and an inactive state (off). Only in the active state, is the gene capable of transcription (producing mRNA).
 
  • #3
Defennder
Homework Helper
2,591
5
But how does this imply that it being switched on in the pancreas only causes the enzyme to be released into the bloodstream?
 
  • #4
jim mcnamara
Mentor
3,909
2,299
This thread is confusing.

Bare bones clotting works by having part of the fibrinogen molecule removed by an enzyme. This creates fibrin. Fibrin is sticky and forms little nets or piles of straw-like fibers which are the glue that holds a clot together. Notice I did not use names of enzymes or any real particulars, on purpose.

Now strictly in terms of the overly simplified model above, do you see the clotting mechanism and how it works?

Let's try another tack. There is a cell type (tissue) in the pancreas, Islets of Langerhans, that manufactures insulin. This is the only place in the body where insulin is made. So, the gene for making insulin exists in every cell in the body, but it "works" only in these little blobs of tissue. It is turned on there. It is not turned on anywhere else. The turning-on is a result of the location in the embryo of the cells that later make up the pancreas, a positional effect.

So, we can have genes turned on or turned off by dint of where the cell lives.
This all makes sense, right? Next, there are other kinds of switches to turn genes off/on. There is no one single switch type.
 
Last edited:
  • #5
Defennder
Homework Helper
2,591
5
It's not the thread that is confusing, everything I have written here is based on the hyperlinked article.

The only question I have, since I think I can understand the 2nd part, is why does the gene being switched on in both the liver and pancreas cause the enzyme to be released in the bloodstream.
 
  • #6
127
0
The only question I have, since I think I can understand the 2nd part, is why does the gene being switched on in both the liver and pancreas cause the enzyme to be released in the bloodstream.
I think you have two pieces of confusion. One is about gene regulation. As others have said, every cell in the human body (and most living things) contains a full set of genes. It is the differring regulation of these genes that makes an eye cell different from a liver cell. Gene regulation is what determines how much mRNA is transcribed from a gene and consequently how much of its protein is made. Gene regulation in humans is extremely complicated but you don't need to really understand it to get this article.

As to the question above: The pancrease produces digestive enzymes that empty into the intestine. So even if it were producing great clotting proteins we'd never get any benefit from that.

The liver, on the other hand, can produce products that are released into the blood stream. If the gene is switched on (ie transcribed) in liver cells than its protein product could potentially be useful in clotting blood.
 
  • #7
127
0
If serine proteases are, as the article states able to self-activate (by mere presence of amino acids in the bloodstream), and if, by the first quoted paragraph, where the serine protease is released into the bloodstream, then wouldn't it be possible for blood to clot itself even when no blood vessels are broken? If so, wouldn't this be disruptive to normal functioning?
My interpretation after reading the second half of the article. This part is providing a hypothesis for how the complex multi-step process of clotting evolved:

What the article doesn't say (but I assume to be true) is that this self activation occurs at a very low level. It's significance comes into play only once the gene duplication occurs. At this point the duplicate gene is able to tolerate mutations which ultimately lead to the evolution of a new protease specialized for cleaving the protein which binds tissue factor.
 
  • #8
Defennder
Homework Helper
2,591
5
Ah, I see, I get the first part now.

The article explains the second part here:

Well, it turns out that it does. First, keep in mind that a primitive clotting system, adequate for an animal with low blood pressure and minimal blood flow, doesn't have the clotting capacity to present this kind of a threat. But just as soon as the occasional clot becomes large enough to present health risks, natural selection would favor the evolution of systems to keep clot formation in check. And where would these systems come from? From pre-existing proteins, of course, duplicated and modified. The tissues of the body produce a protein known as a1-antitrypsin which binds to the active site of serine proteases found in tissues and keeps them in check. So, just as soon as clotting systems became strong enough, gene duplication would have presented natural selection with a working protease inhibitor that could then evolve into antithrombin, a similar inhibitor that today blocks the action of the primary fibrinogen-cleaving protease, thrombin.

In similar fashion, plasminogen, the precursor to a powerful clot-dissolving protein now found in plasma, would have been generated from duplicates of existing protease genes, just as soon as it became advantageous to develop clot-dissolving capability.
The only question I believe that remains is how natural selection and the evolutionary process manages to fine-tune the blood-clotting mechanism such that it would trigger only when substantial blood vessels are broken, as opposed to small stimuli triggering. The article seems only to gloss over this question in the above 2 paragraphs without explaining how.
 
  • #9
127
0
I'm still recovering from new years but when my brain is working I'll try to read the beginning of the article again and figure out your question.
 
  • #10
127
0
That part is true, but earlier it's also explained that gene duplication first gave rise to specialized proteins involved in clotting, not clot dissolving. Preexisting self-cleavage ability for these serine proteases was important in encouraging specialization after gene duplication. This is an example of how evolution often works by fine tuning pre-existing traits.

The article does gloss over exactly how the body knows how to use the "tools" its developed to strike a balance between clotting and blood flow. I looked it up in my physiology text (marieb). Anybody who understands this better than I feel free to add any clarification:

Plasminogen (active form plasmin) is incorporated into the clot complex and becomes a time activated clot dissolver, triggered by tissue plasminogen activator released from endothelial cells. Thrombin itself also activates plasminogen. Damaged endothelial cells inevitably heal, while at the same time plasmin is dissolving the clot.
 

Related Threads on Evolution of blood clotting mechanism

Replies
1
Views
4K
  • Last Post
Replies
2
Views
21K
  • Last Post
Replies
4
Views
2K
Replies
72
Views
7K
Replies
8
Views
4K
  • Last Post
Replies
5
Views
6K
  • Last Post
2
Replies
46
Views
8K
  • Last Post
Replies
4
Views
3K
Top