X-Message-Number: 12240
Date: Wed, 11 Aug 1999 13:05:18 -0700
From: Jeff Davis <>
Subject: Toxicity


In post #12236, 10 Aug 1999, Doug Skrecky wrote:

>For example cryoprotectant toxicity is still something of a
>black art full of mysteries. I'm still finding old reports on  this topic
>which contain information that I was not previously aware of. As you might
>know it is toxicity that is the primary barrier blocking the
>implimentation of vitrification solutions.

How does toxicity manifest?

In some ways toxicity reminds me of "heat".  

At the macroscopic scale--the "big-as-a-breadbox" scale--we have a personal
experience of heat, and that is how we come to know it.  But at the
molecular level, heat is motion--spinning, wiggling, flying-through-space
motion.  At the breadbox scale heat and motion are completely unrelated
(except perhaps in the case of the fastball), and any connection is utterly
unintuitive.  Yet it is clearly fact.

The everday experience of toxicity is "poisonousness".  You injest or
breath or touch something, and events of varying degrees of unpleasantness
follow.  "Unpleasantness" being the fuzzy, not-rigorously-quantified,
qualia-based characterization of "we feel bad".

But what precisely is going on at the cellular/molecular level?  For
example, tetrodotoxin, the key to fugu poisoning, is a molecule which plugs
up one of the ion channels in the cell membrane.  If its presence in that
location is not a covalent bonding situation, ie not a high-strength bond,
one could easily imagine reversing the "damage" merely by grabbing the
"plug" and pulling it out.  Carbon monoxide on the hemoglobin molecule
seems a similar situation.

So what is toxicity precisely?  Are crucial biological molecules, or their
higher level structures plugged, fused, pinched, swollen, distorted,
immobilized, cleaved, unwound, torn, dissolved?  What?  It's so much more
difficult to deal with a problem, or imagine being able to deal with it
when you don't know, well,...what you're dealing with.

Feynman, in his now-famous 1959 lecture "There's plenty of room at the
bottom"  which is widely viewed as marking the birth of nanotech said:

>What are the most central and fundamental problems of biology today? They
are questions like:
>What is the sequence of bases in the DNA? What happens when you have a
mutation? How is
>the base order in the DNA connected to the order of amino acids in the
protein? What is the
>structure of the RNA; is it single-chain or double-chain, and how is it
related in its order of
>bases to the DNA? What is the organization of the microsomes? How are
proteins synthesized?
>Where does the RNA go? How does it sit? Where do the proteins sit? Where
do the amino >acids go in? In photosynthesis, where is the chlorophyll; how
is it arranged; where are the >carotenoids involved in this thing? What is
the system of the conversion of light into chemical >energy? 
>It is very easy to answer many of these fundamental biological questions; 

                                        >you just look at the thing! 

                                                  >You will see
>the order of bases in the chain; 

                                           >you will see the structure 

>of the microsome.


>It would be very easy to make an analysis of any complicated chemical
substance; all
>one would have to do would be to 

                                     >look at it and see where the atoms are. 

Now perhaps this is old hat to many of you, if so I ask your forebearance,
but my point is this:

If, as seems likely, 21CM's improved cryoprotectants reduce structural
damage--by what? 90%?, 99%?, 99.999%?--then we are moving ahead (Surprise!
Surprise!).  Next on the agenda we need to see and understand the
particulars of toxicity so we can get a handle one that part of the
problem.  Ignorance is not a rational basis for pessimism.

Where is there any indication that, as progress continues, we shall not,
rather predictably, arrive at a point where we have the optimally minimized
and balanced structural and toxicity damage and a remediation technology
capable of dealing with it?

Patience is a virtue.  Slow is a relative thing.  The tortoise and the
snail get where they're going.  

Success is a near certainty.

			Best, Jeff Davis

	   "Everything's hard till you know how to do it."
					Ray Charles				

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