From: Robert J. Bradbury (bradbury@aeiveos.com)
Date: Wed Apr 23 2003 - 11:12:14 MDT
On Tue, 22 Apr 2003, Adrian Tymes, responding to my comments
on the costs of genetic engineering wrote:
> Hmm. Correct me if I'm wrong, please, but none of the
> above sounds fundamentally difficult to manufacture.
Some is and some isn't. The plastic consumables are't
difficult to manufacture one just tends to need lots of
them. The enzymes needed to manipulate DNA need to be
of very high quality so those are more expensive. One
may pay several hundred dollars for a very small tube
of enzymes (a few ml).
> Which means, in theory, if one had a large marget of
> would-be genetic engineers, one could set up efficient
> mass production of all of these components, especially
> the consumables and enzymes. The main reason they
> cost so much now is that the effort to set up initial
> manufacturing has to be amortized among a limited set
> of customers.
In part I'd agree. There are probably only of the order
10's of thousands of molecular biologists in the world.
We might be up into the 100's but certainly not millions.
> The problem is that it isn't cheap *right now*.
> Is this correct?
In large part -- if you had many more working in the field
you would get more manufacturers and innovations, patent
expiration & competition would tend to bring the costs
down.
You have to keep in mind how many "specialty" items various
types of research requires. The various reagent manufacturers
all (perhaps 3-5 significant ones) all have catalogs that
are an 1-2 inches thick.
> If so, then it would seem one of the more efficient
> ways to solve the problem would be to document some
> simple examples of the type of engineering you'd like
> to make cheap - basically, recipes that others could
> follow - and give them away.
There are several major books one can by on "protocols"
of various types of molecular biolgy, recombinant DNA
manipulation, cell biology, etc.
> Good point. One could, say, engineer or find a host
> optimized for replication of virii; this would be a
> significant cost, but one-time.
The problem is that people are working with perhaps
half-a-dozen viruses for gene therapies for various
reasons -- each needs a "specialized" cell for
production. So its hard to get the demand to develop
such cells until we start having situations where
we are doing 10's of thousands of gene therapies.
That will be hard because of the problems we've
had getting gene therapies to work and the regulatory
overhead of setting up such trials. I think we've
only had in the clinics or under development a
thousand or so.
> Typical virii are much smaller than typical cells, no?
Yes.
> So, would it be possible to pass the solution,
> containing both virus and cells, through a filter with
> small enough pores that only the virus could fit
> through?
Actually much of the time the viruses are "absorbed" by
cellular processes normally involved in the transport of
various molecules/proteins. That is why viruses tend to
be tissue specific -- they have adapted to make use of
naturally occuring receptors.
You are correct in that the viruses must be filtered out
for any therapeutic applications.
> If limiting copies/overwrites would be difficult, then
> perhaps it might be easier to ensure that overwrites
> would be harmless? Say, design the virii such that,
> if one infects an already infected cell, it will
> merely knock out the previous copy and replace it.
> (Which is why I use the term "overwrite".)
Yes, this would require "site-specific integration".
We know of only 1 virus currently that manages this.
> True, but then you face the problem of integrating
> these secondary nuclei into existing cells, putting
> only one secondary nuclei into each cell instead of
> multiple in one cell and none in its neighbors, making
> sure they divide when they rest of the cell divides,
> et cetera. It seems, on first glance, that by the
> time you solve those problems you'd wind up with
> something very much like a non-self-reproducing virus
> anyway.
The *difference* is that with secondary nuclei (SN) you can
carry at least 600 genes, perhaps as many as 4000.
With viruses you are limited to probably 200 or even
6-50 probably in most viruses currently (all gene
theapies I've seen I believe are only attempting
a single gene).
You can also make the secondary nuclei (SN) programs
complex enough that they could detect the other SN
and regulate their own copy number. Making them
divide based on the normal division signals would
not be difficult. Getting them to separate properly
is what is difficult -- even normal eukaryotic cells
don't manage to separate the replicated chromosomes
properly each time.
But most cells in the body do not replicate -- at least
not frequently. Really only the stem cells and the
entire Red blood cell/White blood cell systems do so.
So one could receive substantial benefits from such
architectures before one solved the replication
problem.
Robert
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