* UNANSWERED QUESTIONS: RESPONSE *

Anthony J. Pelletier, Ph.D. anthonyp at scripps.edu
Fri Jun 7 16:02:40 EST 1996


In article <4p7dc4$t16$1 at mhade.production.compuserve.com>, Margaret Fowler
<101722.35 at CompuServe.COM> wrote:

> 1. Discourtesy, assumptions of ignorance, and emotive remarks are no
> substitute for measured argument and evidence. 

Agreed.

> Each of these quest-
> ions highlights a contradiction *within* current views; for example,
>     (a) everyone agrees that intracellular movements can be seen by
> low power light microscopy in living cells, yet most people also
> believe that there is a cytoskeleton, which would not permit such
> movements;

I don't understand your conlusion.   Why do you conclude that the
cytoskeleton would interfere with intracellular movement?  On the one
hand, you say below that the cytoskeleton does not exist.  But, you seem
pretty sure of its properties.  Is it necessarily so that a network of
fibers is refractory to intracellular movement?  Personally, I can imagine
many mechanisms wherein such a network, given the appropriate motor
system, could facilitate intracellular movement.  So it is in no way
obvious that the presence of intracellular movement is inconsistent with a
cytoskeleton.  It is inconsistent if and only if the cytoskeleton is a
rigid network whose effective pore size is smaller than the molecules that
must diffuse through it.  I've seen no evidence of this, and in fact much
evidence to the contrary.  
As a somewhat strained analogy, particles the size of electrons have
little problem passing through apparently solid material such as wood.
In fact, a quick calculation of diffusion coefficients tells you that a
molecule the size of a protein could not diffuse from one side of a cell
to another in any time reasonable in comparison to the cells life. 
Moreover, movement must be directional. This would seem to make necessary
the existence of some structure along which molecules can be transported
actively.

Then, there are the data to consider.  Just to pick one, how do you
explain the incorporation of fluorescently labeled tubulin into what
appear to be fillements in the cell?  what would you call these
microtubules if not a cytoskeleton?  
It would take far too long to go into even a small fraction of the data. 
However, let's take my favorite molecules, Integrins, which we think
violate two of your rules in that they are transmembrane proteins and that
they associate with elements of the cytoskeleton.  Biochemistry,
immunofluorescence and genetic evidence all support the idea that these
proteins have a portion outside the membrane and one inside, that the
region inside assciates with proteins we consider part of the
cytoskeleton, and that these associations are necessary to maintain cell
shape.  Are you saying all these data must be flawed because they don't
fit with your first-principles argument?


>     (b) most people believe in the Second Law of Thermodynamics, yet
> in subcellular fractionation they change the entropy of their systems
> (homogenise and centrifuge), and assume that this does not change the
> free energy, which drives all the biochemical reactions they are
> studying, and at the same time, they have refused for fifty years to
> do the necessary control experiments to find out by how much;

No biochemist worth a damn believes this.  We all are accutely aware that
removing the enzymes from their environment can grossly alter the
reactions, for many reasons including but not limitted to the ones you
cite.  That's why we use all these hand-waving terms like "local high
concentration" to account for an an entropy term cannot quantify.  
as for the "proper controls,"  we do try.  


> 3. I have always suggested alternative and testable hypotheses, not
> open to the criticisms of current views, for example, how to local-
> ise biochemical activities without disruption of tissue, the struc-
> ture of the living cell, the cellular structure of the central
> nervous system, the passage of excitability from one neuron to
> another, etc, etc.

Many of us try to do this.  What you have said above does not give me
great confidence in your methods.  However, I would love to read how, for
example, we could better examine the biochemistry even something "simple"
like glycolysis in the cell.

> 
> 4. The fundamental questions I must raise with the Internet
> cytologists are:
>     'By what criteria are questions improper?'

Your questions are not improper.  They may assume facts not in evidence,
or disregard many things for which there is evidence, but they are not
improper.
In science, the only time a question is improper (as a scientific
question) is when the person asking it does not accept the possibility of
being wrong.
I hope you acknowledge at least the formal possibility that you may be wrong?

 
>     'Do all academics have a duty to address the difficulties and
> apparent contradictions of their own views?'

sure.  That is a truism

>     'Do they believe that progress can be made without examining
> their own views?'

no, of course not.  not any good ones.  Do you examine the possibility
that your views are wrong?

>     'Would they disagree that a good academic should answer all
> these questions in the affirmative?'

well...your first question was not framed in a yes/no format, the answer
to the second is "yes" and the answer to the third is "no."

As for re-checking others findings, there is some limit,practically, in
what I can do.  I certainly do not take their conclusions without critical
examination of the data.  But I cannot repeat all their experiments. 
There are many published papers I have read whose conclusions I think are
not supported by the data.  I consider these as I design and interpret my
experiments.

One ground rule I will have, if we are to have any discussion:
Disagreeing with you is not the same as failing to examine data critically.

Ok, so, i can examine data, look at both side of the argument, and still
think you are wrong, if that turns out to be the case, and my scientific
integrity is still intact.

-- 
Anthony J. Pelletier, Ph.D.
Assistant Member, Department of Cell Biology
The Scripps Research Institute
La Jolla, CA

anthonyp at scripps.edu



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