directed evolution

From: Damien Broderick (
Date: Wed Jan 17 2001 - 20:10:46 MST

At 07:35 AM 17/01/01 -0800, Dan Ust wrote:

>Note: by directed evolution or orthogenesis is _not_ meant that some mind is
>directing it. It just means that evolution has a direction -- at least, in
>some cases. The cause of this could be no more mystifying that

I believe you've changed the definition mid-course. The more usual
connotation of directed evolution, sans theology, might be closer to the
program under investigation by the Arnold group, led by Frances H. Arnold,
Professor of Chemical Engineering and Biochemistry, Division of Chemistry
and Chemical Engineering, Caltech. E.g.:

< To appreciate the challenge of designing and carrying out a successful
directed protein evolution experiment, it is important to underscore the
powerful combinatorial features of this system. A typical enzyme is a
linear chain of N amino acids (N is usually several hundred), and there are
20 possible amino acids at each position in the chain. Thus the `sequence
space' of possible proteins is huge beyond the imagination (20^N ). Even in
4 billion years, nature has had a chance to explore but a tiny fraction of
these possibilities. A laboratory exploration of this vast space of
sequences and their corresponding functions must obviously be severely
limited and carefully guided [Arnold, 1998a]. Because much of sequence
space will be devoid of the desired function and probably even folded
proteins, it is best to direct the evolution of one (or more) existing
enzymes rather than look for function in random peptide libraries.

Evolution is often referred to as a hill-climbing exercise in the fitness
landscape of sequence space
[Eigen, 1986; Kauffman, 1993]. The fitnesses (performance, for laboratory
evolution) of the proteins in
sequence space make up this landscape, whose most basic features are still
quite unknown. The
landscape for laboratory evolution will be different for each property or
collection of properties
undergoing evolution. I have argued [Arnold, 1996; Arnold, 1998a] that an
uphill climb in a
landscape is more likely to be successful if it can take place in small
steps (one or two amino acid
substitutions). The high dimensionality of the surface (there are 19^N
one-mutant neighbors of any
given sequence) offers many opportunities to find improved mutants. While
we may never reach the
'global optimum', the improvements achieved by taking even a simple random
up-hill walk via single
amino acid mutations often yields useful results. A widely effective
evolutionary strategy, illustrated
in Figure 2, is one in which the steps are small (preferably single amino
acid substitutions in each
generation) and multiple such mutations are accumulated, either
sequentially or by recombination
[Stemmer, 1994; Stemmer, 1997], to acquire the desired function [Arnold,
1996; Arnold, 1998a]. Such
an approach is compatible with a low level of random mutagenesis over the
entire gene. An alternative approach is to direct a much higher level of
random mutation to a relatively small region of the gene [Black et al.,
1996]. Both approaches have their advantages. Mutagenesis over the entire
gene allows discovery of unanticipated solutions (a common experience).
More intense, directed mutation, however, may yield novel combinations of
amino acid substitutions, combinations that would be inaccessible by single
step walks because the intermediates are unfavorable. >

This thread began with the hoary proposition that human minds are far too
wonderful not to have been designed by a Designer (that is, by implication,
a sort of Cosmic Professor Arnold). That's a far stronger claim than the
observation that if water freezes to falling snow, in this universe, under
common earthlike conditions, you always find symmetrical snowflakes rather
than blotchy lumps or small white tigers: self-organization? sure; divine
or pantheistic intervention? I rather doubt it.

>Of course, it seems to have gone the way of most threads here. People
>telling jokes. People attacking each other's character and intelligence.

That's because the use of the term in the main stem of the thread was (or
seemed) crypto-theological. What other response than parody and mockery do
you expect on this list?

Damien Broderick

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