From: Josh Bembenek (jbembe@hotmail.com)
Date: Sat Aug 10 2002 - 16:25:50 EDT
{Lindsay}
> "And it was doing it in a life form which didn't _need_ oxygen carried,
> much. It lived in the ocean and it preceded the divergence of plants and
> animals. It didn't exactly have four-chambered heart, and lungs, and
> capillaries. We know this because globins are found so universally, in
> lifeforms both with and without blood."
{Josh}
> ---This may certainly free the restraints required for hemoglobin
evolution.
> If it was originally only marginally required and only marginally
> advantageous to the organism, then it may have had more chance to get
going.
> Do you think that this is globally applicable? It would seem that
there
> are many functions within the machinery necessary for life that cannot be
> minimized back to a time when they weren't required or important. The
first
> organisms may not have needed globins very much, but they certainly
depended
> upon thousands of other critical enzymes for their survival and
> reproduction. For these other critical enzymes, was there also some
earlier
> unnecessary timepoint where they could be evolved and yet not required?
If
> so, this would imply that every product made by every enzymatic pathway
> critical for life was available for the first cell/replicative code to
use
> before the enzymes capable of producing them existed. Is there any
reason
> to think this is correct? How could we prove/disprove this assertion?
{Lindsay}
Yawn. Abiogenesis is not my department, nor do I subscribe to the theory
that if we don't know everything yet, then it's time to despair. I
decline to let you move the goalposts every time I succeed at answering a
question. (We discussed globin: now you want me to explain thousands of
things, and I suppose your doubts are alive until *every* *last* *one* is
convincing.) And I consider it fallacious that Intelligent Design people
try to deal only in things that happened *more* than a billion years ago.
What, God went away a billion years ago? Or are they merely trying to
cover up the fact that when something happened recently enough for the
evidence to still be around, the evidence displease them?
{Note} He is minimizing the problems with his unsupported claims and
arguing a strawman. Since he cannot actually provide a direct answer to the
issue of products needed for a cell before the enzymes capable of producing
them exist, he avoids it and gets defensive. Just because hemoglobin was
"not needed much" does not eliminate the overwhelming problems indicated
below about deriving hemoglobin sequences, here I was simply agreeing that
it would "help" if it were "not needed much." Not being needed much,
therefore, does not give us anything close to a mechanistic answer or much
insight into the problem. Nor is it something supported by factual
published evidence in peer-reviewed journals. No one has proven just how
much (I wonder what your assay would be for degree of need) simpler
organisms may or may not need their particular hemoglobin molecules, they
could be very important for organism survival. The citations he provided
show the original discovery of these "derivative" hemoglobins. I don't
believe it is currently understood how essential they are, he certaintly
doesn't cite anything, simply dogmatically declares his faith.
{Note} What follows is the body of the original message without any further
comments from Dr. Lindsay as I wrote it to him in response originally:
{Lindsay}
> "Well, some act as oxygen binding/inactivation proteins - as occurs today
in
> some bacteria. Those probably evolved from hemoglobins that did electron
> transport. And sure enough, some modern bacteria use them for just that.
> Specifically, the electron transport carrier cytochrome B family. And
then
> there's nitric oxide:"
{Josh}
> ---I see the issue in this way, all globins have the same fold and
sequence
> identity. There is nothing obvious to me about the relationship between
all
> the globins that give indications as to how the globin fold itself ever
> evolved. There is a point in sequence identity before which any given
> sequence can adapt the globin fold, and previous to it being a globin I
do
> not understand how this hypothetical protein would have function or even
> fold properly. All the papers you listed highlight the fact that all
globin
> genes, while they may vary as much as 80% of the positions (leghemoglobin
> vs. vertebrate globin in Hardison, R. C., PNAS 93, 5675-5679) maintain
the
> same three-dimensional structure, have specific residues that are highly
> invariable, and additional restraints for certain portions of the
molecule
> to remain hydrophobic, etc. for the globin to be intact! From the
articles
> mentioned, not only do all globins share three dimensional structure
> similarities, but they all share the ability of binding oxygen, with some
> members gaining additional functionality. My question about this issue
> ignores the ability of a given protein to perform a given function and
gain
> additional functions, rather my question is focused on how do you drive
the
> formation of the original function in the absence of the ability to
perform
> that function to any degree whatsoever, BY MEANS OF DARWINIAN EVOLUTION
(which supposedly is the generally accepted and proven mechanism for
biological change)? When you are randomly synthesizing a globin molecule by
way of randomly connecting amino acids or sequences, and you only have part
of the globin
> molecule in your sequence, it does not appear that it can provide any
> selective advantage towards carrying oxygen before it is capable of
folding
> into a globin fold. To clarify my thinking on this issue, here is a
> relevant section from "Biochemistry" by Lubert Stryer (p. 418):
>
> "The way out of this dilemma is to recognize the power of cumulative
> selection. Richard Dawkins, in The Blind Watchmaker, asked how long it
would
> take a monkey poking randomly at a typewriter to reproduce Hamlet's
remark to Polonius, "Methinks it is like a wasel." An astronomically large
number of keystrokes, of the order of 10^40, would be required. However,
suppose that we preserved each correct character and allowed the monkey to
retype only the wrong ones.
> In this case, only a few thousand keystrokes on average would be needed.
The
> crucial difference between these cases is that the first employs a
> completely random search [the hemoglobin number] whereas in the second,
> partially correct intermediates are retained. The essence of protein
> folding is the retention of partially correct intermediates. However, the
> protein folding problem is much more difficult that the one presented to
our
> simian Shakespeare. First, proteins are only marginally stable. The
> free-energy difference between the folded and unfolded states of a
typical
> 100-residue protein is 10kcal/mol. The average stabilization per residue
is
> only 0.1kcal/mol, which is less than random thermal energy
(RT=0.6kcal/mol
> at room temperature). This means that correct intermediates, especially
> those formed early in folding, can be lost. The analogy is that the
monkey
> would be quite free to undo its correct keystrokes. Second, the criterion
of
> correctness is not a residue-by-residue scrutiny of conformation by an
> omniscient observer [as Dawkins analogy provides with the computer
program]
> but rather the total free energy of the transient species. Intermediates
can
> be scored only by their free energies. Third, some intermediates, called
> kinetic traps, have a favorable free energy but are not on the path to
final
> folded protein form. No wonder then that protein folding is such an
> intriguing problem for both theoriticians and experimentalists."
>
> In sum, this indicates that the restraints for the development of even a
> simple globin fold would be enormous. The number of counterproductive,
> unfolded, disadvantageous sequences that stand in between any given
random
> sequence and the first functional advantageous globin molecule seems
quite
> large. Dawkins analogy closes its eyes as the initial random sequence
> traverses these dangerous protein folding intermediates and kinetic
> favorable non-folded traps, and completely ignores the technical
difficulty
> involved with creating a folded, soluble protein, much less originating
any
> fold capable of properly binding a porphyrin ring! The analogy also
assumes that each such intermediate has selective advantage in the
replicating system it is a part of. Obtaining a protein
> molecule capable of binding any porphyrin ring (ignoring whatever
processes
> are required to synthesize the first porphyrin ring so that it would be
conveniently
> available for use when the ancient precursor porphyrin-ring-binding
protein
> serendipitously emerged from the chaotic world of
> non-functional-protein-folding intermediates) must be an enormous feat
all
> on its own. What evidence or indication makes such a scenario possible?
> Protein folding issues indicate to me that the origin of functional
proteins
> is beyond the ability of random sequence generation and slight sequence
> modification until the final functional sequence is happened upon,
because
> there is no utility for these intermediates. (Hence my curiosity for the
> support of your previous statement that hemoglobin was doing something
else,
> but not very well on its way to becoming hemoglobin.) If anything, this
> process would create many more molecules that inhibit the process rather
> than augment it taking into account these issues from protein folding
> dynamics. The range of theoretical "optimized multiple desirable
outcomes"
> seems quite narrow within the possibilities, but similarly the sequence
> space that needs to be traversed from random sequence to functional
sequence
> seems even more limited with all the kinetic-trap pitfalls and non-folded
> products. For similar reasons, the following statement you made:
>
> <First, function is more mutable than you imagine.>
>
> Does not correlate well in my mind with the above section from Stryer.
Not
> only do the examples you listed for highly mutable proteins with diverse
functionality involve proteins that already have a given
> stable fold, but as far as I am aware, they are rare occurrences. Allen
Orr
> remarks in his criticism of Behe's work, that (Boston Review @
> http://bostonreview.mit.edu/bostonreview/br21.6/orr.html ):
>
> "First it will do no good to suggest that all the required parts of some
> biochemical pathway popped up simultaneously by mutation. Although this
> "solution" yields a functioning system in one fell swoop, it's so
hopelessly
> unlikely that no Darwinian takes it seriously. As Behe rightly says, we
gain
> nothing by replacing a problem with a miracle. Second, we might think
that
> some of the parts of an irreducibly complex system evolved step by step
for
> some other purpose and were then recruited wholesale to a new function.
But
> this is also unlikely. You may as well hope that half your car's
> transmission will suddenly help out in the airbag department. Such things
> might happen very, very rarely, but they surely do not offer a general
> solution to irreducible complexity."
>
> So it appears that Dr. Orr disagrees with the ability of proteins to be
> evolved for "some other purpose and were then recruited wholesale to a
new
> function," as you have described, and concludes that the occurrence of
this,
> i.e. proteins being recruited for new function, occurs "very very
rarely."
> What evidence or resource could I investigate to find a conclusion for
this
> matter one way or the other? I tend to agree with Dr. Orr, but I would
be
> highly interested in what evidence compells you to view the issue
> differently.
>
> In closing, consider the following sequence of events:
>
> Completely Random Sequence (no function)
> --Transition I-->
> Stably folded, biologically active sequence (with function)
> --Transition II-->
> Optimized Diversity of Function derived from similarly folded sequences
>
> You have argued that evidence from the second transition; i.e. the
> generation of diversity of function from an original stable protein fold
> proves that the first transition occurred. I would be very interested in
> learning of the evidence or proof that exists directly demonstrating the
> occurrence of the first transition. So far, what I've seen consists of
> computer/ mathematical models, which do not directly relate to the
problem
> of protein folding and functional sequence intermediates (and are also
not
> extremely clear to me on first investigation and therefore beyond my full
> comprehension). This is the core of my skepticism of Dawkins' analogy
and
> the fundamental problem I have envisioning how this scenario could occur.
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