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Overview of
all studies: Because of the largely unexpected transformational
power of molecular manufacturing, it is urgent to understand the issues
raised. To date, there has not been anything approaching an adequate study
of these issues. CRN's recommended series of thirty
essential studies is organized into five sections, covering fundamental
theory, possible technological capabilities, bootstrapping potential,
product capabilities, and policy questions. Several preliminary conclusions
are stated, and because our understanding points to a crisis, a parallel
process of conducting the studies is urged.
CRN is actively
looking for researchers interested in performing or assisting with this
work. Please contact CRN Research Director Chris
Phoenix if you would like more information or if you have comments
on the proposed studies.
Study
#9
What
will be required to develop biological programmable manufacturing and
products?
This study
would explore the various steps involved in harnessing biology to produce
engineered products. [Answers in italics are provided
by Robert
Bradbury.]
Subquestion
How much
time and effort would be required to develop the ability to design predictable
protein folding, possibly by introducing novel amino acids?
Preliminary answer
Unknown, but a novel
protein fold has been successfully designed and tested. Increasing computer
power will make this rapidly easier.
It
would not be difficult to integrate novel amino acids using a standard
protein synthesis robot. It is more difficult to integrate to integrate
them into bacteria, but it has been done.
Subquestion
How difficult
would it be to automate all steps of new-protein synthesis? How long would
a fully automated system need to produce and characterize a new protein?
Preliminary answer
New
protein synthesis is already automated (its a volume/cost issue that can
be a hang-up -- which is why bacteria are used to produce things like
insulin, antibiotics, etc.). The NSF is pushing rapidly on the automation
of the characterization problem (everything from X-ray crystallography
to computers figuring out the structure). I've read that they are trying
to push it to 30,000 structures per year. Though I'm not sure if I can
believe that number -- if you look at the growth of the contents of PDB
it may be a reality in the near future.
There are structures
that are difficult to characterize -- these are usually proteins that
normally reside in cell membranes of one form or another. So it's a limited
subset -- perhaps 20-30% of all proteins. Some novel techniques have been
reported for dealing with this but this is ultimately just going to require
a lot of work and clever ideas.
Subquestion
What software
support must be developed to allow design and testing of novel protein-based
machines?
Preliminary answer
Tough
question -- we already have the software to design proteins (and the machines
to manufacture at least the smaller ones). Testing isn't really a problem. The
problem is the creation of a 'novel' machine design.
Subquestion
How much
time and/or research will be required before we know how cell signaling/differentiation/gene
expression works?
Preliminary answer
We
know how gene expression works reasonably well (something like three classes
of transcription factors, the structures of which tend to be very standardized,
etc.). We also know a lot about signaling and differentiation. We've
got hundreds of extracellular molecules and receptors pinned down at this
point. The problem is the molecules involved within the cell from
the membrane to the nucleus. These are very complex. There is
a company in Germany that has worked out much of this in yeast and the
#1 priority on the NIH Nanomedicine goal list is to extend this to determine
all of the protein complexes in humans.
Subquestion
How can cell
toxicity or metabolic interference from novel chemicals be predicted and
avoided?
Preliminary answer
This is relevant
because one method of protein synthesis involves using gene-spliced cells
to synthesize the protein. However, there are ways of manufacturing proteins
that do not require cells.
The
simple answer is knowledge of the structures of most if not all of the
enzymes, receptors, etc. in the body, knowledge of the structure of the
novel chemicals and a heck of a lot of computer power to see when/how
the structures can interfere. A more complex answer would involve
actual toxicity tests at a MEMS scale level to determine when chemicals
interfere with the functioning of a protein. (This isn't too different
from the work that has been done to synthesize large chemical/drug libraries
-- but requires that one understand the metabolic pathways involved and
devise individual tests to see when there is interference.)
The situation is
extremely urgent. The stakes are unprecedented, and the world is unprepared.
The basic findings of these studies should be verified as rapidly as possible
(months, not years). Policy preparation and planning for implementation,
likely including a crash development program, should begin immediately.
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