Behe's response to Lenski's first post

What you can or cannot understand is quite beside the point. The studies I linked to clearly show that APOB-deficient mice have male fertility defects. Behe should have mentioned this, as this observation tempers the notion that polar bears have only 50% of the APOB activity of brown bears.

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You are wrong

in Farese et al it says

In contrast to our apo-B knockout mice, developmental abnormalities have not been observed in human apo-B deficiency syndromes. What could account for this apparent difference in the phenotypes of apo-B deficiency in mice and humans? One possible explanation relates to developmental differences between the two species. In both species, apo-B is expressed in the yolk sac; however, the yolk sac plays a different developmental role in the two species. In the mouse, the yolk sac becomes part of the membranes that surround the developing embryo and contact the maternal tissues early in gestation, whereas in human embryos the yolk sac is a less prominent organ that becomes an appendage attached near the allantoic mesoderm. Thus, it is possible that apo-B produced by the yolk sac in the mouse might play a more important role in facilitating the delivery of lipids or fat-soluble vitamins to the developing embryo early in gestation.

For the similar reason, it is not necessarily mean that decreased activity in APOB gene yields fertility defects.

@Edgar_Tamarian, did you bother to read the two studies I linked to?

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  1. J Clin Invest. 1995 Nov;96(5):2152-61.

apo B gene knockout in mice results in embryonic lethality in homozygotes and
neural tube defects, male infertility, and reduced HDL cholesterol ester and apo
A-I transport rates in heterozygotes.

Huang LS(1), Voyiaziakis E, Markenson DF, Sokol KA, Hayek T, Breslow JL.

Author information:
(1)Laboratory of Biochemical Genetics and Metabolism, Rockefeller University, New
York 10021, USA.

apo B is a structural constituent of several classes of lipoprotein particles,
including chylomicrons, VLDL, and LDL. To better understand the role of apo B in
the body, we have used gene targeting in embryonic stem cells to create a null
apo B allele in the mouse. Homozygous apo B deficiency led to embryonic
lethality, with resorption of all embryos by gestational day 9. Heterozygotes
showed an increased tendency to intrauterine death with some fetuses having
incomplete neural tube closure and some live-born heterozygotes developing
hydrocephalus. The majority of male heterozygotes were sterile, although the
genitourinary system and sperm were grossly normal. Viable heterozygotes had
normal triglycerides, but total, LDL, and HDL cholesterol levels were decreased
by 37, 37, and 39%, respectively. Hepatic and intestinal apo B mRNA levels were
decreased in heterozygotes, presumably contributing to the decreased LDL levels
through decreased synthesis of apo B-containing lipoproteins. Kinetic studies
indicated that heterozygotes had decreased transport rates of HDL cholesterol
ester and apo A-I. As liver and intestinal apo A-I mRNA levels were unchanged,
the mechanism for decreased apo A-I transport must be posttranscriptional.
Heterozygotes also had normal cholesterol absorption and a normal response of the
plasma lipoprotein pattern to chronic consumption of a high fat, high
cholesterol, Western-type diet. In summary, we report a mouse model for apo B
deficiency with several phenotypic features that were unexpected based on
clinical studies of apo B-deficient humans, such as embryonic lethality in
homozygotes and neural tube closure defects, male infertility, and a major defect
in HDL production in heterozygotes. This model presents an opportunity to study
the mechanisms underlying these phenotypic changes.

DOI: 10.1172/JCI118269
PMCID: PMC185864
PMID: 7593600 [Indexed for MEDLINE]

  1. Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):10903-7.

A novel functional role for apolipoprotein B in male infertility in heterozygous
apolipoprotein B knockout mice.

Huang LS(1), Voyiaziakis E, Chen HL, Rubin EM, Gordon JW.

Author information:
(1)Department of Medicine, Columbia University, College of Physicians and
Surgeons, New York, NY 10032, USA. lh99@columbia.edu

Male infertility, affecting as many as 10% of the adult population, is an
extremely prevalent disorder. In most cases, the cause of the condition is
unknown, and genetic factors that might affect male fertility, other than some
sequences on the Y chromosome, have not been identified. We report here that male
mice heterozygous for a targeted mutation of the apolipoprotein B (apo B) gene

exhibit severely compromised fertility. Sperm from these mice failed to fertilize
eggs both in vivo and in vitro. However, these sperm were able to fertilize eggs
once the zona pellucida was removed but displayed persistent abnormal binding to
the egg after fertilization. In vitro fertilization-related and other experiments
revealed reduced sperm motility, survival time, and sperm count also contributed
to the infertility phenotype. Recognition of the infertility phenotype led to the
identification of apo B mRNA in the testes and epididymides of normal mice, and
these transcripts were substantially reduced in the affected animals. Moreover,
when the genomic sequence encoding human apo B was introduced into these animals,
normal fertility was restored. These findings suggest that this genetic locus may
have an important impact on male fertility and identify a previously unrecognized
function for apo B.

PMCID: PMC38255
PMID: 8855280 [Indexed for MEDLINE]

You are NOT reading my post

in Farese et al it says

In contrast to our apo-B knockout mice, developmental abnormalities have not been observed in human apo-B deficiency syndromes . What could account for this apparent difference in the phenotypes of apo-B deficiency in mice and humans? One possible explanation relates to developmental differences between the two species. In both species, apo-B is expressed in the yolk sac ; however, the yolk sac plays a different developmental role in the two species. In the mouse, the yolk sac becomes part of the membranes that surround the developing embryo and contact the maternal tissues early in gestation, whereas in human embryos the yolk sac is a less prominent organ that becomes an appendage attached near the allantoic mesoderm. Thus, it is possible that apo-B produced by the yolk sac in the mouse might play a more important role in facilitating the delivery of lipids or fat-soluble vitamins to the developing embryo early in gestation.

For a similar reason, it is not necessarily mean that decreased activity in APOB gene yields fertility defects.

Otherwise, you have to show that in polar bears the yolk sac plays the same developmental role as in mice.

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Well, you are not reading mine. Where did Behe address this?

Where did Behe address this? I have not found out where he justified this representation of the author’s conclusions.

Where has he addressed this? I have not yet seen it?

We responded in detail to every point Behe has raised. Often we had answered him before he even made the objection. We are just asking for the same courtesy.

@Edgar_Tamarian, it seems that the squid ink from ENV is successfully confused and disoriented you. This does not take scientific expertise to understand.

  1. Behe did not correctly represent the views of the author’s of the study.
  2. When this was pointed out, he called us incompetent.
  3. He never dealt with this fundamental critique.

Instead, he ignored our point, and jumped when to arguing he was correct.

  1. To his credit, he did add new information (not into his book) that raises questions about a simplistic answer, but creates another scientific problem for him

I do not expect you to grasp #4, but #1-#3 are straightforward. He has not responded.

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I’m not surprised a close read of those papers shows he left an important fact out. @Art, would you like to write up an explanation of the dialogue with me that doesn’t respond to Behe as much explain the exchange to observers in an engaging way? I think this will be fun, and would want to coauthor it with. I know @Nlents is getting tired of Behe, but if we focus this on explaining how biological reasoning works to the public, that could a broader approach.

What do you think?

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One of the interesting findings in the study on mice is that animals that were homozygous (i.e. have two copies) for the knockout ApoB mutation did not make it past the fetal stage. They had severe developmental issues. I would assume that there are many polar bears who are homozygous for the mutations in question, and they have no developmental issues. This is a big red flag. I don’t think the mouse study can be directly applied to polar bears.

I’m in for that kind of thing. Once again, what Behe has done is an extreme cherry pick… in a paper detailing all the problems with APOB-deficient mice, he found one result that could, maybe, if you squint long enough, indicate that reduced APOB activity improves cholesterol clearance. The problem is that the paper didn’t look at cholesterol clearance, so it doesn’t support his position directly. Another problem is that simply having lower plasma triglycerides does not indicate overall better cardiovascular health. A person (or a mouse) can be very very sick, but their LDL levels look good (low), particularly if they are undernourished. In fact, when someone is critically ill, the chemical composition of the blood can start to go haywire in unpredictable ways. Some of the individual items may look fine in isolation, but the overall picture will be a picture of very poor health, as those mice were. Honestly, Behe might have a very lucrative second career in the picking of cherries - he has a real talent for it!

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Um, the yolk sac likely has nothing to do with the phenotype Behe is ignoring.

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I think Behe would argue that the “damaging” mutations, even in homozygotes, only lead to a 50% reduction in activity (whatever that may be).

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On a different tangent, a 50% increase in activity can also be deleterious in different circumstances.

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True enough. This applies to a few of the genes I work on …

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@NLENTS you should collaborate with @swamidass and @Art on this as it will help you to become a more widely known, lesser known scientist. :sunglasses:

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You are again NOT reading my post**

in Farese et al it says

In both species, apo-B is expressed in the yolk sac ; however, the yolk sac plays a different developmental role in the two species. In the mouse, the yolk sac becomes part of the membranes that surround the developing embryo and contact the maternal tissues early in gestation, whereas in human embryos the yolk sac is a less prominent organ

An aside that I hope doesn’t distract too much…
By chance, I’ve just sat through a few seminars that discuss functional roles of the ‘disordered’ regions of proteins. One role that’s interesting (to me) is in forming lose connections or gel-like regions in the cell. This type of configuration has interesting impacts on regulation. What’s nice is that we’re developing the biophysical tools necessary to understand more about their dynamics (a nice application for computational modelling, @swamidass).

The relationship to this discussion is…
We often talk about disrupting the folding of an ‘organized’ protein as having a negative or ‘damaging’ effect. And certainly, in some cases that can increase the protein’s turnover in the cell. However, there are also clearly instances where this change is a positive effect. And in fact, that we know of roles for disordered regions suggests that changes that disrupt parts of a protein’s structure is another way for ‘functions’ to be acquired and/or changed.

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In your own words, @Edgar_Tamarian, could you explain the connection between the yolk sac and sperm functionality? That may help clear up some confusion here.

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In Reality, you are cutting the quote to sound Behe what you like to him be sound
in Darwin devolves we read the opposite.

Since few experiments can be done with grumpy polar bears, they analyzed the changes by computer . They determined that the mutations were very likely to be damaging —that is, likely to degrade or destroy the function of the protein that the gene codes for…Computer analysis of the multiple mutations of the gene showed that they too were almost certainly damaging to its function. In fact, of all the mutations in the seventeen genes that were most highly selected, about half were predicted to damage the function of the respective coded proteins

as also Behe explains

Professor Lenski points out (as I repeatedly do in the book) that the computer analysis is a prediction that a particular mutation will or won’t be damaging; it is not an experimental demonstration

He precisely addressed here

The APOB gene of polar bears is mutated with changes that were predicted by computer methods to be damaging. A 1995 study showed that a mouse model that had one copy of the APOB gene knocked out actually had lower plasma cholesterol levels and increased resistance to hypercholesterolemia from a high fat diet. If the polar bear mutations acted to lower the activity of its own APOB, a result similar to that for the mouse might be expected. Thus there is no good reason to speculate about new functions

Trollhoffer recently called me “somewhat prominent.” I dunno. I think I preferred “lesser known.” But at least I’m not “some other guy” (@art). I’m actually surprised that Behe didn’t remember him from the T-urf13 bit.

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I think someone needs to remind Behe of the First Law of Holes.

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