RMS Replies to "The Stallman Factor"

Ryan Amos writes "RMS has replied to the article "The Stallman Factor," as posted on Slashdot about a week ago. In specific, his replies deal with the University of Texas SIGLinux naming fiasco and Bitkeeper. As always with RMS, an interesting read."

Comments

Re:Stallman is a fucking ass

[Anonymous Coward]

Ok, deeeeep breaths...

Re:He can't be serious

[ComaVN]

Moderator abuse galore... How the hell is this offtopic?

Anyway, it seems to me it's the same thing as Gates not giving a speech at a hypothetical internet user group, because it's not called MS-Internet.
(Hey, IE is the predominant tool for accessing the internet, so he could claim that "by convention", whatever that means, it should be MS-Internet)

Stallman is doing more damage than good with this pathetic ego trip of his.

Sorry to drag MS into this flaimbait-ridden discussion, but it was the first example that sprang to mind.

RMS Contradicts Himself

[idonotexist]

Throughout the article, though he at times (mainly at the beginning of the article) uses GNU/Linux, RMS refers to GNU/Linux as Linux on numerous occassions.

How can we consider his argument if he, himself, does not actively practice what he preaches?

Re:Slashdotted already

[Anonymous Coward]

The first journal article on molecular nanotechnology, reproduced
here by permission of the author.

Special thanks from IMM to Jim Lewis for preparing this Web document and
writing the following introduction to the paper:

Presented here is the complete text of the landmark paper that K. Eric Drexler
published in the
in 1981. In this paper he advanced the proposal that the molecular machinery
found in living systems demonstrates the feasibility of doing advanced molecular
engineering to produce complex, artificial molecular machines. A key insight
is his proposal that the engineering problem of designing
proteins to fold in a predetermined way is much easier than the scientific
problem of predicting how natural proteins fold. Appended to this paper
is a short perspective written by Drexler in 1988 in which he notes substantial
progress made in the area of protein structure design compared
to protein structure .

--Jim Lewis

Affiliations listed below for the author are out of date. Current affiliation:
Research Fellow, Institute for Molecular Manufacturing, Palo Alto, California.

[Editor's Note: This page has been optimized for Netscape
2 and later. If you are using a browser, such as Netscape 1.1, that does
not support the html tag for superscripts, please be aware that an
number like "2x109" is meant to be scientific notation for "2
times ten raised to the 9th power," etc.] 1771">Implications for the present

of errors can be minimized through fault-tolerant
design, as in macroscopic engineering.

The emphasis on devices that have general capabilities should be taken in
the spirit of early work on the theoretical capabilities of computers, which
did not attempt to predict such practical embodiments as specialized or
distributed computation systems. The present argument, however, will proceed
from step to step by close analogies between the proposed steps and past
developments in nature and technology, rather than by mathematical proof.
We commonly accept the feasibility of new devices without formal proof,
where analogies to existing systems are close enough: consider the feasibility
of making a clock from zirconium. The detailed design of many specific devices
to render them describable by dynamical equations would be a task of another
order (consider designing a clock from scratch) and appears unnecessary
to the establishment of the feasibility of certain general capabilities.
Protein design
Biochemical systems exhibit a "microtechnology" quite different
from ours: they are not built down from the macroscopic level but up from
the atomic. Biochemical microtechnology provides a beachhead at the molecular
level from which to develop new molecular systems by providing a variety
of "tools" and "devices" to use and to copy. Building
with these tools, themselves made to atomic specifications, we can begin
on the far side of the barrier facing conventional microtechnology.

What can be built with these tools? Gene synthesis i4).

At present, the design of protein systems as complex as a ribosome seems
an awesome task. Indeed, chemists cannot yet predict the three-dimensional
conformation of a natural protein from its amino acid sequence, an ability
that might seem requisite to the design of new proteins. Two considerations
suggest that this obstacle is surmountable: first, the continuing improvement
in protein science and, second, the difference between natural science and
design engineering.

Regarding the first, computer simulation of protein molecules in solution shows promise. As computer technology and
chemical knowledge improve, simulations will increase in accuracy, speed,
and size. Improvement promises new insight into protein behavior and may
permit the designer to modify (simulated) molecules quickly and to observe
their behavior directly.

Regarding the second consideration, natural scientists seek a more general
understanding than design engineers require. Science seeks the ability to
predict the conformations of all natural polypeptides. In attempting this,
protein chemists can search for a minimum-energy chain conformation (in
hope that the protein assumes not a local but a global minimum-energy conformation)
or can attempt to follow the chain-folding
mechanism to find the final conformation (7).
Prediction will be easier if the natural conformation has outstanding stability
or if its folding mechanism proceeds in a sequence of strongly preferred
steps. Unfortunately, natural selection accepts polypeptides that have natural
conformations of low stability (in energetic terms) so long as they exhibit
long lifetimes on the cellular time scale (or renature readily). Similarly,
natural selection accepts any folding process so long as the chain reaches
its natural conformation with essentially 100% yield. Moreover, random mutations
are unlikely to enhance the stability of a particular conformation (or the
predictability of its folding mechanism). Thus, natural proteins tend to
accumulate disruptive changes until they reach the threshold of poor stability
or reduced yield of the natural conformation; only then does natural selection
come into play. Thus, it is little wonder that chemists cannot yet predict
the conformations of natural proteins; they are not designed to fold predictably.

Engineers (in contrast to scientists) need not seek to understand all proteins
but only enough to produce useful systems in a reasonable number of attempts.
An engineer designing a protein that has 1000 amino acids may choose among
some 10randomly selected
sequences would yield a predictable conformation, yet this tiny fraction
represents a vast number of proteins. Through use of strategically placed
charged groups, polar groups, disulfide bonds, hydrogen bonds, and hydrophobic
groups, the engineer should be able to design proteins that not only fold
predictably to a stable structure (sometimes) but that serve a planned function
as well. Even a low success rate will lead to an accumulation of successful
designs. Thus, the difficulties encountered in predicting the conformations
of natural proteins do not seem insurmountable obstacles to protein engineering.

Computer modeling and chemical understanding of biological targets have
already found use in pharmaceutical design (8),
and an artificial 34-residue polypeptide designed to interact with RNA has
been synthesized and found active (9). It has
been proposed to give microcircuitry special sensitivities by adsorbing
engineered proteins onto selected surfaces (10).
The promise of enzyme design in chemical engineering is evident. As protein
science has great promise and difficulties in understanding natural proteins
need not block engineering, the substantial payoffs for improved capabilities
should lead to development of protein design technology. It would be foolish
to underestimate the time and effort that will be required to develop basic
design capabilities and then a broad family of working molecular devices;
still, the path seems clear to achieving the capabilities exhibited by existing
biochemical systems, by copying their features if need be.

A comparison of biochemical to macroscopic components will show the possibilities
of the former by analogy to the latter (Table 1).
With structural members, moving parts, bearings, and motive power, versatile
mechanical systems can be built. Molecular assemblages of atoms can act
as solid objects, occupying space and holding a definite shape. Thus, they
can act as structural members and moving parts. Sigma bonds that have low
steric hindrance can serve as rotary bearings able to support ~ 10-9
N. A line of sigma bonds can serve as a hinge. Conformation-changing proteins
(such as myosin) can serve as sources of motive power for linear motion;
the reversible motor of the bacterial flagellum can serve as a source of
motive power for rotary motion. The existence of this range of components
in nature indicates that power-driven mechanical systems can be constructed
on a molecular scale.

Move things Conformation-changing proteins, actin/myosin
Motors Turn shafts Flagellar motor
Drive shafts Transmit torque Bacterial
flagella Bearings Support moving parts

Sigma bonds Containers Hold fluids
Vesicles Pipes Carry fluids Various
tubular structures Pumps Move fluids Flagella,
membrane proteins Conveyor belts Move components

RNA moved by fixed ribosome (partial analog) Clamps
Hold workpieces Enzymatic binding sites Tools
Modify workpieces Metallic complexes, functional groups

Production lines Construct devices Enzyme
systems, ribosomes Numerical control systems Store
and read programs Genetic system

By analogy with macroscopic devices, feasible molecular machines presumably
include manipulators able to wield a variety of tools. Thermal vibrations
in typical structures are a modest fraction of interatomic distances; thus,
such tools can be positioned with atomic precision. As present microtechnology
(2) can lay down conductors on a molecular
scale (10 nm) and molecular devices can respond to electric potentials (through
conformation changes, etc.), such devices can be controlled by human operators
or macroscopic machines. Further, by analogy with biological sensors, molecular
scale instruments can evidently produce macroscopic signals, indicating
the feasibility of feedback control in molecular manipulations.

Together, these arguments indicate the feasibility of devices able to move
molecular objects, position them with atomic precision, apply forces to
them to effect a change, and inspect them to verify that the change has
indeed been accomplished. It would be foolish to minimize the time and effort
that will be required to develop the needed components and assemble them
into such complex and versatile systems. Still, given the components, the
path seems clear.

Ordinary chemical synthesis relies on thermal agitation to bring reactant
molecules in solution together in the correct orientation and with sufficient
energy to cause the desired reaction. Enzyme-like molecular machines can
hold reactants in the best relative positions as bonds are strained or polarized.
Like some enzymes, they can do work on reactant molecules to drive reactions
not otherwise thermodynamically favored.

These are clearly techniques of great power, yet the synthetic capabilities
of systems based on polypeptide chains might seem limited by amino acid
properties. However, enzymes show that other molecular structures bound
to the polypeptide (such as metal ions and complex ring structures) (11)

can extend protein capabilities. The range of such tools is large and greater
than found in nature. Thus, the synthetic capabilities of enzymes set only
a lower bound on the capabilities of engineered protein systems. Indeed,
as tool-wielding protein systems can control the chemical environment of
a reaction site completely, they should be able, at a minimum, to duplicate
the full range of moderate-temperature synthetic steps achieved by organic
chemists. Further, where chemists must resort to complex strategies to make
or break specific bonds in large molecules, molecular machines can select
individual bonds on the basis of position alone. Conventional organic chemistry
can synthesize not only one-, two-, and three-dimensional covalent structures
but also exotic strained and fused rings. With the addition of controlled
site-specific synthetic reactions, a broad range of large complex structures
can doubtless be built.

Still, the synthetic abilities of protein machines will be limited by their
need for a moderate temperature aqueous environment (although applied forces
can sometimes replace or exceed thermal agitation as a source of activation
energy and reaction sites and reactive groups can be protected from the
surrounding water, as in some enzymatic active sites). These limits may
be sidestepped by using the broad synthetic capabilities outlined above
to build a second generation of molecular machinery whose components would
not be coiled hydrated polypeptide chains but compact structures having
three-dimensional covalent bonding. There is no reason why such machines
cannot be designed to operate at reduced pressure or extreme temperatures;
synthesis can then involve highly reactive or even free radical intermediates,
as well as the use of mechanical arms wielding molecular tools to strain
and polarize existing bonds while new molecular groups are positioned and
forced into place. This may be done at high or low temperature as desired.
The class of structures that can be synthesized by such methods is clearly
very large, and one may speculate that it includes most structures that
might be of technological interest.
Firmness of the argument
The development path described above should lead to advanced molecular machinery
capable of general synthesis operations. As the results of this path can
be shown to have consequences for the present, it is of interest to discuss
the degree of confidence that should be placed in its feasibility.

It might be argued that complex protein or nonprotein machines are impossible
or useless, on the grounds that, if they were possible and useful, organisms
would be using them. A similar argument would, however, conclude that bone
is a better structural material than graphite composite, that neurons can
transmit signals faster than wires, and that technology based on the wheel
is impossible or useless. Nature has been constrained less by what is physically
possible than by what could be evolved in small steps. Thus, the absence
of a proposed kind of molecular machinery in organisms in no way suggests
its infeasibility.

To deny the feasibility of advanced molecular machinery, one must apparently
maintain either (i) that design of proteins will remain infeasible indefinitely,
or (ii) that complex machines cannot be made of proteins, or (iii) that
protein machines cannot build second-generation machines.

In light of the expected improvements in computation, the simplified task
of design engineers (compared with scientists), the possibilities offered
by sheer trial-and-error modification of natural proteins, and the progress
already made in protein design, the first seems difficult to maintain. Further,
even if protein design were to prove intractible (because of difficulties
in predicting conformations), this would in no way preclude developing an
alternative polymer system with predictable coiling and using it as a basis
for further development.

In light of the presence of the needed components for mechanical devices
in the cell, the second seems difficult to maintain. Indeed, the cytoskeleton
provides a fair counterexample.

In light of the results of synthetic organic chemistry and the ability of
molecular machines to make reactions site specific, it seems difficult to
maintain that nonprotein machine components cannot be built and assembled.

Each of the development steps outlined above seems closely analogous to
past steps taken by nature or by technology. Each of these steps can be
accomplished in many ways. To argue their infeasibility would seem to require
some general principle precluding success, and it is difficult to see what
such a principle might be like. Thus, the claim that advanced molecular
technology can be developed seems well founded.

Although the existence of molecular machinery in cells indicates the feasibility
of some sort of artificial molecular machinery, errors in assembly might
limit the synthesis of structures of great complexity. In the cell, molecular
machinery uses DNA to direct the assembly of DNA and other molecules. In
some eukaryotic cells, DNA directs DNA synthesis with an error rate of ~
10-11 per nucleotide added (12).
As engineers commonly design systems to function reliably with many more
failed components than 1 in 1011, such an error rate seems no
barrier to the construction of quite complex devices.

The possibility of low error rates is not surprising. For synthesis systems
permitting error detection and correction (such as DNA synthesis), the net
error rate in assembly can be reduced to roughly the product of the raw
error rate in assembly and the rate at which errors are falsely identified
as correct. As no uncertainty principle prohibits accurate discrimination
between objects of different kinds (such as correctly and incorrectly assembled
molecular structures), no limits to the detection and correction of errors
are apparent.
Applications to computation
Molecular technology has obvious application to the storage and processing
of information. A crude approach would involve literal "molecular machinery"
patterned on the Babbage machine. In a more subtle approach, bits could
be represented by protons, bound electrons, reactive groups, or conformation
changes and transferred by movement of protons or of well-localized electrons
(13), excitons, or phonons. The range of plausible
device speeds is suggested by the 10-6 -sec turnover time for
a fast enzyme, by the 10-13 -sec scale of collisional interactions
(11), and by the 10-16 sec taken
for an electron to cross an interatomic distance at a typical Fermi velocity.

It seems highly likely that a cubic cell 0.1 micrometers on a side (containing
some 108 optimally arranged atoms) can hold a bit or perform
a logic operation and, at the same time, transmit bits through itself to
provide communication from cell to cell in a lattice. If so, then computers
can be built with at least 1015 active elements per cubic centimeter.
In a well-designed computer (with elements closer to their true technological
limit and not laid out in regular cubical cells), this volume estimate should
prove quite conservative. Elements so small will be sensitive to radiation
damage; to be reliable, systems will require a large measure of redundancy.

Concern might be raised about the cost of such intricately patterned matter,
either because of labor or energy requirements. It seems clear, however,
that molecular-scale production systems can be completely automated (what
use is there for hands?). Thus, labor costs of production (including production
of additional production equipment) can approach zero. The energy needed
to produce molecularly engineered material will generally be greater than
the energy needed to produce ordinary materials of similar bulk composition,
but analogy suggests that the energy cost need not be vastly greater than
for the production of biological materials. In many cases (e.g., advanced
computers or any of a number of applications not discussed here), the unique
value of the products would make such energy costs unimportant, even if
energy costs remained high.
Some biological applications
Molecular devices can interact directly with the ultimate molecular components
of the cell and thus serve as probes of unique value in studying processes
within the cell. Further, molecular devices can characterize a frozen cell
in essentially arbitrary detail by removal and characterization of successive
layers of material (atomically thin layers, if desired). Although the amount
of data involved is large (a typical cell contains billions of protein molecules),
the physical bulk of a device able to store and manipulate this amount of
data will be quite small.

The change of temperature and water distribution during freezing modifies
cell structures in several ways, primarily by physical displacement of structures
by ice crystals and denaturation of proteins by concentration of solutes
in the residual liquid (14). With frozen tissue,
knowledge of normal structures (membrane geometries, natural protein structures)
and analysis of frozen structures (position of ice crystals, position of
denatured proteins) should permit quite accurate reconstruction of the nature
of the tissue before freezing.

Such procedures would have special utility in analyzing the structure of
tissue in the brain. Unlike, say, muscle or liver tissue, the function of
brain tissue depends on the detailed three-dimensional structure of intertwined
cells and their interfaces. The freezing process is far too slow to stop
such dynamic processes as action potentials and synaptic transmission; short-term
memory, however, is suspected to involve chemical modification of the neurons,
and long-term memory is believed to involve the growth and modification
of neuronal structures, particularly synapses (15).
At the modest freezing rates possible in substantial pieces of tissue, ice
crystals may be expected to nucleate and grow in the intercellular fluid,
displacing the cell membranes as they do so (16).
Electron micrographs, however, show that synapses (like many intercellular
junctions) involve complementary structures on both sides of the intercellular
gap, which should provide information enough to reconstruct the pre-freezing
configurations of the cells almost regardless of ice crystal locations.

The ability to reconstruct the prefreezing structure of tissue, when combined
with the general synthetic capabilities outlined above, will make feasible
the physical restoration of tissue damaged by ordinary freezing through
characterization, reconstruction, and restoration of successive segments
of frozen material. Although restored to a frozen condition, such tissue
would lack the characteristic damage caused by the freezing process. As
many tissues can survive the gross insult of ordinary freezing (17),
it seems likely that most could survive freezing followed by repair. The
remaining mode of damage would seem to be denaturation of proteins sensitive
to cold alone during the thawing process. Should cell components of some
species prove sensitive to short periods of cold, they could presumably
be modified to resemble those of hardier species (hamsters can survive freezing
of half their body water; ref. 17) without changing
either cell function or DNA.
Implications for the present
The existence of a path to an advanced molecular technology has implications
for the present. As with all technologies, long-range promise should tend
to increase interest in undertaking the early steps, even beyond the interest
springing from more immediate benefits. The longer the expected wait, however,
the less the interest.

On the other hand, molecular engineering of materials and devices can extend
the capabilities of technology many fold in many areas. The implications
of the feasibility of molecular technology are important to present day
speculations concerning the probable behavior (and likelihood of existence)
of extraterrestrial technological civilizations. Similarly, those concerned
with the long-range future of humanity must concern themselves with the
opportunities and dangers arising from this technology. Finally, the eventual
development of the ability to repair freezing damage (and to circumvent
cold damage during thawing) has consequences for the preservation of biological
materials today, provided a sufficiently long-range perspective is taken.
Conclusion
Development of the ability to design protein molecules will, by analogy
between features of natural macromolecules and components of existing machines,
make possible the construction of molecular machines. These machines can
build second-generation machines able to perform extremely general synthesis
of three-dimensional molecular structures, thus permitting construction
of devices and materials to complex atomic specifications. This capability
has implications for technology in general and in particular for computation
and characterization, manipulation, and repair of biological materials.

I thank C. Peterson, P. Morrison, J. Lettvin, A. Kantrowitz, and C. Walsh
for their comments and criticism.



1. Feynman,
R. (1961) in Miniaturization, ed. Gilbert, H. D.
(Reinhold, New York), pp. 282-296.

2. Krumhansl, J. A. & Pao, Y. H. (1979)
Phys. Today 32 (11), 25-32.

3. Itakura, K. & Riggs, A. D. (1980) Science
209, 1401-1405.

4. Nomura, M. & Held, W. (1974) in Ribosomes,
eds. Nomura, M., Tissiers, A. & Lengyel, P. (Cold Spring Harbor Laboratory,
Cold Spring Harbor, NY), pp. 193-203.

5. McCammon, J. A., Gelin, B. R. & Karplus,
M. (1977) Nature (London) 267, 585-590.

6. Scheraga, H. A. (1978) in Versatilty
of Proteins, ed. Li, C. H. (Academic, New York), pp. 119-132.

7. Karplus, M. & Weaver, D. L. (1976) Nature
(London) 260, 404-406.

8. Gund, P., Andose, J. D., Rhodes, J. B. &
Smith, G. M. (1980) Science 208,

1425-1431.

9. Gutte, B., Dannigen, M. & Wittschieber,
E. (1979) Nature (London) 281, 650-655.

10. Anonymous (1980) Semicond. Int.
3 (5), 10.

11. Walsh, C. (1979) Enzymatic Reaction
Mechanisms (Freeman, San Francisco), pp. 33, 38.

12. Drake, J. (1969) Nature (London)
221, 1132.

13. Chance, B., Mueller, P., DeVault, D. &
Powers, L. (1980) Phys. Today 33 (10), 32-38.

14. Fennema, O. R. (1973) in Low-Temperature
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O. R., Powrie, W. D. & Marth, E. H. (Dekker, New York), pp. 476-503.

15. Entingh, D., Dunn, A., Glassman, E., Wilson,
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16. Fennema, O. R. (1973) in Low-Temperature
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PROTEIN ENGINEERING:
A 1988 view of some 1981 predictions
K. Eric Drexler

Visiting Scholar, Stanford University. Box 60775, Palo Alto, CA 94306

A 1981 paper [1] discussed de novo protein design as part of a long-term
strategy for developing complex molecular devices and systems. It presented
arguments against the view that the fold-design problem is an extension
of the classical (and still unsolved) fold-prediction problem (i.e.,
predicting folds from sequences without homologous models), a view which
has discouraged efforts at design.

Fold prediction is a scientific problem: it must deal with naturally evolved
sequences, but natural selection's 'design goals' enforce only the physical
reliability of folding -- not its human predictability. This results in
folds of only minimal stability. Fold design, in contrast, is an engineering
problem. Protein engineers, exploiting their freedom of design, can work
with sequences artificially selected for superior predictability and stability
of folding. These observations indicated that "the difficulties encountered
in predicting the conformations of natural proteins do not seem insurmountable
obstacles to protein engineering" [1].

In accord with the implications of this argument, we have seen the successful,
de novo design of a globular protein (alpha-4) [2,3] while the classical
fold prediction problem remains unsolved [4]. Likewise confirmed has been
the suggestion that design can increase protein stability beyond that enforced
by natural selection. In recent years, deliberate single-residue modifications
have raised protein stabilities through a variety of mechanisms [5,6]. Owing
to design choices consistently biased toward stability, the protein alpha-4
has a stability of 22 kcal/mole, substantially greater than the 4-9 kcal/mole
of typical natural proteins of similar size [3].

Successful protein engineering marks a milestone in a research agenda leading
toward capabilities of broad technological significance [1,7].
References

[1] K. E. Drexler, "Molecular engineering: An approach to the development
of general capabilities for molecular manipulation." Proc.
Nat. Acad. Sci., 78: 5275-5258 (1981).

[2] S. P. Ho and W. F. DeGrado, "Design of a 4-Helix bundle protein:
Synthesis of peptides which self-associate into a helical protein."
J. Am. Chem. Soc., 109: 6751-6758 (1987).

[3] L. Regan and W. F. DeGrado, "Characterization of a helical protein
designed from first principles." Science, 241:
976-978 (1988).

[4] T. E. Creighton, "The protein-folding problem." Science,
240: 267, 344 (1988).

[5] L. J. Perry and R. Wetzel, "Disulfide bond engineered into T4 lysozyme:
stabilization of the protein toward thermal inactivation." Science,
226: 555-557 (1984).

[6] B. W. Matthews, H. Nicholson, and W. J. Becktel, "Enhanced protein
thermostability from site-directed mutations that decrease the entropy of
unfolding." Proc. Nat. Acad. Sci., 84: 6663-6667
(1987), and included references.

[7] K. E. Drexler, Engines of Creation, Anchor/Doubleday
(New York, 1986).