Molecular Machines:
Experimental Support for the Design Inference

by Michael J. Behe

A Series of Eyes

How do we see? In the 19th century the anatomy of the eye was known in great
detail and the sophisticated mechanisms it employs to deliver an accurate picture
of the outside world astounded everyone who was familiar with them. Scientists
of the 19th century correctly observed that if a person were so unfortunate as to
be missing one of the eye’s many integrated features, such as the lens, or iris,
or ocular muscles, the inevitable result would be a severe loss of vision or
outright blindness. Thus it was concluded that the eye could only function if
it were nearly intact.

As Charles Darwin was considering possible objections to his theory of evolution
by natural selection in The Origin of Species he discussed the problem of the eye in
a section of the book appropriately entitled "Organs of Extreme Perfection and
Complication." He realized that if in one generation an organ of the complexity
of the eye suddenly appeared, the event would be tantamount to a miracle. Somehow, for
Darwinian evolution to be believable, the difficulty that the public had in
envisioning the gradual formation of complex organs had to be removed.

Darwin succeeded brilliantly, not by actually describing a real pathway that
evolution might have used in constructing the eye, but rather by pointing to
a variety of animals that were known to have eyes of various constructions,
ranging from a simple light sensitive spot to the complex vertebrate camera eye,
and suggesting that the evolution of the human eye might have involved similar
organs as intermediates.

But the question remains, how do we see? Although Darwin was able to persuade
much of the world that a modern eye could be produced gradually from a much
simpler structure, he did not even attempt to explain how the simple light sensitive
spot that was his starting point actually worked. When discussing the eye Darwin
dismissed the question of its ultimate mechanism1:

How a nerve comes to be sensitive to light hardly concerns us more than how
life itself originated.

He had an excellent reason for declining to answer the question: 19th century
science had not progressed to the point where the matter could even be approached.
The question of how the eye works–that is, what happens when a photon of light
first impinges on the retina–simply could not be answered at that time. As a matter
of fact, no question about the underlying mechanism of life could be answered
at that time. How do animal muscles cause movement? How does photosynthesis
work? How is energy extracted from food? How does the body fight infection?
Nobody knew.

Calvinism

Now, it appears to be a characteristic of the human mind that when it is unconstrained
by knowledge of the mechanisms of a process, then it seems easy to imagine simple
steps leading from non-function to function. A happy example of this is seen
in the popular comic strip Calvin and Hobbes. Little boy Calvin is always having
adventures in the company of his tiger Hobbes by jumping in a box and traveling
back in time, or grabbing a toy ray gun and "transmogrifying" himself into various
animal shapes, or again using a box as a duplicator and making copies of himself
to deal with worldly powers such as his mom and his teachers. A small child
such as Calvin finds it easy to imagine that a box just might be able to fly
like an airplane (or something), because Calvin does not know how airplanes
work.

A good example from the biological world of complex changes appearing to be
simple is the belief in spontaneous generation. One of the chief proponents
of the theory of spontaneous generation during the middle of the 19th century
was Ernst Haeckel, a great admirer of Darwin and an eager popularizer of Darwin’s
theory. From the limited view of cells that 19th century microscopes provided,
Haeckel believed that a cell was a "simple little lump of albuminous combination
of carbon," 2 not much different from a piece of microscopic Jello. Thus it
seemed to Haeckel that such simple life could easily be produced from inanimate
material. In 1859, the year of the publication of The Origin of Species, an explorator
y vessel, H.M.S. Cyclops, dredged up some curious looking mud from the sea bottom.
Eventually Haeckel came to observe the mud and thought that it closely resembled
some cells he had seen under a microscope. Excitedly he brought this to the
attention of Thomas Henry Huxley, Darwin’s great friend and defender. Huxley,
too, became convinced that it was Urschleim (that is, protoplasm), the progenitor
of life itself, and Huxley named the mud Bathybius Haeckelii after the eminent proponent
of abiogenesis.

The mud failed to grow. In later years, with the development of new biochemical
techniques and improved microscopes, the complexity of the cell was revealed.
The "simple lumps" were shown to contain thousands of different types of organic
molecules, proteins, and nucleic acids, many discrete subcellular structures, specialized
compartments for specialized processes, and an extremely complicated architecture.
Looking back from the perspective of our time, the episode of Bathybius Haeckelii
seems silly or downright embarrassing, but it shouldn’t. Haeckel and Huxley were
behaving naturally, like Calvin: since they were unaware of the complexity of
cells, they found it easy to believe that cells could originate from simple
mud.

Throughout history there have been many other examples, similar to that of Haeckel,
Huxley and the cell, where a key piece of a particular scientific puzzle was
beyond the understanding of the age. In science there is even a whimsical term
for a machine or structure or process that does something, but the actual mechanism
by which it accomplishes its task is unknown: it is called a ‘black box.’ In
Darwin’s time all of biology was a black box: not only the cell, or the eye,
or digestion, or immunity, but every biological structure and function because,
ultimately, no one could explain how biological processes occurred.

Ernst Mayr, the prominent biologist, historian, and guiding force behind the
neo-Darwinian synthesis, has pointed out that 3:

Any scientific revolution has to accept all sorts of black boxes, for if one
had to wait until all black boxes are opened, one would never have any conceptual
advances.

That is true. But in earlier days when black boxes were finally opened science,
and sometimes the whole world, appeared to change. Biology has progressed tremendously
due to the model that Darwin put forth. But the black boxes Darwin accepted
are now being opened, and our view of the world is again being shaken.

Proteins

In order to understand the molecular basis of life it is necessary to understand
how things called "proteins" work. Although most people think of protein" as
something you eat, one of the major food groups, when they reside in the body
of an uneaten animal or plant proteins serve a different purpose. Proteins are the
machinery of living tissue that builds the structures and carries out the chemical
reactions necessary for life. For example, the first of many steps necessary
for the conversion of sugar to biologically-usable forms of energy is carried
out by a protein called hexokinase. Skin is made in large measure of a prot
ein
called collagen. When light impinges on your retina it interacts first with
a protein called rhodopsin. As can be seen even by this limited number of examples
proteins carry out amazingly diverse functions. However, in general a given
protein can perform only one or a few functions: rhodopsin cannot form skin
and collagen cannot interact usefully with light. Therefore a typical cell conta
ins thousands and thousands of different types of proteins to perform the many
tasks necessary for life, much like a carpenter’s workshop might contain many
different kinds of tools for various carpentry work.

What do these versatile tools look like? The basic structure of proteins is
quite simple: they are formed by hooking together in a chain discrete subunits
called amino acids. Although the protein chain can consist of anywhere from
about 50 to about 1,000 amino acid links, each position can only contain one
of twenty different amino acids. In this way they are much like words: words
can come in various lengths but they are made up from a discrete set of 26 letters.
Now, a protein in a cell does not float around like a floppy chain; rather, it
folds up into a very precise structure which can be quite different for different
types of proteins. When all is said and done two different amino sequences–two
different proteins–can be folded to structures as specific as and different from
each other as a three-eighths inch wrench and a jigsaw. And like the household
tools, if the shape of the proteins is significantly warped then they fail to
do their jobs.

The Eyesight of Man

In general, biological processes on the molecular level are performed by networks
of proteins, each member of which carries out a particular task in a chain.

Let us return to the question, how do we see? Although to Darwin the primary
event of vision was a black box, through the efforts of many biochemists an
answer to the question of sight is at hand. 4 When light strikes the retina
a photon is absorbed by an organic molecule called 11-cis-retinal, causing it to
rearrange within picoseconds to trans-retinal. The change in shape of retinal
forces a corresponding change in shape of the protein, rhodopsin, to which it
is tightly bound. As a consequence of the protein’s metamorphosis, the behavior
of the protein changes in a very specific way. The altered protein can now interact
with another protein called transducin. Before associating with rhodopsin, transducin
is tightly bound to a small organic molecule called GDP, but when it binds to
rhodopsin the GDP dissociates itself from transducin and a molecule called GTP,
which is closely related to, but critically different from, GDP, binds to transducin.

The exchange of GTP for GDP in the transducinrhodopsin complex alters its behavior.
GTP-transducinrhodopsin binds to a protein called phosphodiesterase, located
in the inner membrane of the cell. When bound by rhodopsin and its entourage,
the phosphodiesterase acquires the ability to chemically cleave a molecule called cGMP.
Initially there are a lot of cGMP molecules in the cell, but the action of the
phosphodiesterase lowers the concentration of cGMP. Activating the phosphodiesterase
can be likened to pulling the plug in a bathtub, lowering the level of water.

A second membrane protein which binds cGMP, called an ion channel, can be thought
of as a special gateway regulating the number of sodium ions in the cell. The
ion channel normally allows sodium ions to flow into the cell, while a separate
protein actively pumps them out again. The dual action of the ion channel and pump
proteins keeps the level of sodium ions in the cell within a narrow range. When
the concentration of cGMP is reduced from its normal value through cleavage
by the phosphodiesterase, many channels close, resulting in a reduced cellular
concentration of positively charged sodium ions. This causes an imbalance of
charges across the cell membrane which, finally, causes a current to be transmitted
down the optic nerve to the brain: the result, when interpreted by the brain, is vision.

If the biochemistry of vision were limited to the reactions listed above, the
cell would quickly deplete its supply of 11-cis-retinal and cGMP while also becoming
depleted of sodium ions. Thus a system is required to limit the signal that
is generated and restore the cell to its original state; there are several mechanisms
which do this. Normally, in the dark, the ion channel, in addition to sodium
ions, also allows calcium ions to enter the cell; calcium is pumped back out
by a different protein in order to maintain a constant intracellular calcium
concentration. However, when cGMP levels fall, shutting down the ion channel
and decreasing the sodium ion concentration, calcium ion concentration is also
decreased. The phosphodiesterase enzyme, which destroys cGMP, is greatly slowed
down at lower calcium concentration. Additionally, a protein called guanylate
cyclase begins to resynthesize cGMP when calcium levels start to fall. Meanwhile,
while all of this is going on, metarhodopsin II is chemically modified by an
enzyme called rhodopsin kinase, which places a phosphate group on its substrate.
The modified rhodopsin is then bound by a protein dubbed arrestin, which prevents
the rhodopsin from further activating transducin. Thus the cell contains mechanisms
to limit the amplified signal started by a single photon.

Trans-retinal eventually falls off of the rhodopsin molecule and must be reconverted
to 11-cis-retinal and again bound by opsin to regenerate rhodopsin for another
visual cycle. To accomplish this trans-retinal is first chemically modified
by an enzyme to transretinol, a form containing two more hydrogen atoms. A second
enzyme then isomerizes the molecule to 11-cis-retinol. Finally, a third enzyme
removes the previouslyadded hydrogen atoms to form 11-cis-retinal, and the cycle
is complete.

To Explain Life

Although many details of the biochemistry of vision have not been cited here,
the overview just seven is meant to demonstrate that, ultimately, this is wha
t it means to ‘explain’ vision. This is the level of explanation that Biological
science eventually must aim for. In order to say that some function is understood,
every relevant step in the process must be elucidated. The relevant steps in
biological processes occur ultimately at the molecular level, so a satisfactory
explanation of a biological phenomenon such as sight, or digestion, or immunity,
must include a molecular explanation. It is no longer sufficient, now that the
black box of vision has been opened, for an ‘evolutionary explanation’ of that
power to invoke only the anatomical structures of whole eyes, as Darwin did
in the 19th century and as most popularizers of evolution continue to do today.
Anatomy is, quite simply, irrelevant. So is the fossil record. It does not matter
whether or not the fossil record is consistent with evolutionary theory, any
more than it mattered in physics that Newton’s theory was consistent with everyday
experience. The fossil record has nothing to tell us about, say, whether or how the
interactions of 11-cis-retinal with rhodopsin, transducin, and phosphodiesterase
could have developed step-by-step. Neither do the patterns of biogeography matter,
or of population genetics, or the explanations that evolutionary theory has
given for rudimentary organs or species abundance.

"How a nerve comes to be sensitive to light hardly concerns us
more than how
life itself originated," said Darwin in the 19th century. But both phenomena
have attracted the interest of modern biochemistry. The story of the slow paralysis
of research on life’s origin is quite interesting, but space precludes its retelling
here. Suffice it to say that at present the field of originoflife studies has
dissolved into a cacophony of conflicting models, each unconvincing, seriously
incomplete, and incompatible with competing models. In private even most evolutionary
biologists will admit that science has no explanation for the beginning of life. 5

The purpose of this paper is to show that the same problems which beset origin-of-life
research also bedevil efforts to show how virtually any complex biochemical
system came about. Biochemistry has revealed a molecular world which stoutly
resists explanation by the same theory that has long been applied at the level of the
whole organism. Neither of Darwin’s black boxes–the origin of life or the origin
of vision or other complex biochemical systems–has been accounted for by his
theory.

Irreducible Complexity

In The Origin of Species Darwin stated 6:

If it could be demonstrated that any complex organ existed which could not possibly
have been formed by numerous, successive, slight modifications, my theory would
absolutely break down.

A system which meets Darwin’s criterion is one which exhibits irreducible complexity. By irreduci
ble complexity I mean a single system which is composed of several interacting
parts that contribute to the basic function, and where the removal of any one
of the parts causes the system to effectively cease functioning. An irreducibly
complex system cannot be produced gradually by slight, successive modifications of
a precursor system, since any precursor to an irreducibly complex system is
by definition nonfunctional. Since natural selection requires a function to
select, an irreducibly complex biological system, if there is such a thing, would
have to arise as an integrated unit for natural selection to have anything to
act on. It is almost universally conceded that such a sudden event would be
irreconcilable with the gradualism Darwin envisioned. At this point, however, ‘irreducibly
complex’ is just a term, whose power resides mostly in its definition. We must
now ask if any real thing is in fact irreducibly complex, and, if so, then are
any irreducibly complex things also biological systems.

Consider the humble mousetrap (Figure 1). The mousetraps that my family uses
in our home to deal with unwelcome rodents consist of a number of parts. There
are: (1) a flat wooden platform to act as a base; (2) a metal hammer, which
does the actual job of crushing the little mouse; (3) a wire spring with extended
ends to press against the platform and the hammer when the trap is charged;
(4) a sensitive catch which releases when slight pressure is applied; and (5)
a metal bar which holds the hammer back when the trap is charged and connects
to the catch. There are also assorted staples and screws to hold the system
together.

[IMAGE]

Figure 1. A household mousetrap. The working parts of the trap are labeled. If
any of the parts are missing the trap does not function.

If any one of the components of the mousetrap (the base, hammer, spring, catch,
or holding bar) is removed, then the trap does not function. In other words,
the simple little mousetrap has no ability to trap a mouse until several separate
parts are all assembled.

Because the mousetrap is necessarily composed of several parts, it is irreducibly
complex. Thus, irreducibly complex systems exist.

Molecular Machines

Now, are any biochemical systems irreducibly complex? Yes, it turns out that
many are.

Earlier we discussed proteins. In many biological structures proteins are simply
components of larger molecular machines. Like the picture tube, wires, metal
bolts and screws that comprise a television set, many proteins are part of structures
that only function when virtually all of the components have been assembled.
A good example of this is a cilium. 7
 Cilium animation??? Figure 2a. Animation of a Cilium

Cilia are hairlike organelles on the surfaces of many animal and lower plant
cells that serve to move fluid over the cell’s surface or to "row" single cells
through a fluid. In humans, for example, epithelial cells lining the respiratory
tract each have about 200 cilia that beat in synchrony to sweep mucus towards
the throat for elimination. A cilium consists of a membrane-coated bundle of
fibers called an axoneme. An axoneme contains a ring of 9 double microtubules
surrounding two central single microtubules. Each outer doublet consists of a ring of
13 filaments (subfiber A) fused to an assembly of 10 filaments (subfiber B).
The filaments of the microtubules are composed of two proteins called alpha
and beta tubulin. The 11 microtubules forming an axoneme are held together by three
types of connectors: subfibers A are joined to the central microtubules by radial
spokes; adjacent outer doublets are joined by linkers that consist of a highly
elastic protein called nexin; and the central microtubules are joined by a connecting
bridge. Finally, every subfiber A bears two arms, an inner arm and an outer
arm, both containing the protein dynein.

But how does a cilium work? Experiments have indicated that ciliary motion results
from the chemically-powered "walking" of the dynein arms on one microtubule
up the neighboring subfiber B of a second microtubule so that the two microtubules
slide past each other (Figure 2a and b). However, the protein cross-links between
microtubules in an intact cilium prevent neighboring microtubules from sliding
past each other by more than a short distance. These cross-links, therefore,
convert the dynein-induced sliding motion to a bending motion of the entire axoneme.

 [IMAGE]??????????????? Figure 2b. Schematic drawing of part of a cilium. The power stroke of the
motor protein, dynein, attached to one microtubule, against subfiber B of a
neighboring microtubule causes the fibers to slide past each other. The flexible
linker protein, nexin, converts the sliding motion to a bending motion.

Now, let us sit back, review the workings of the cilium, and consider what it
implies. Cilia are composed of at least a half dozen proteins: alpha-tubulin,
beta-tubulin, dynein, nexin, spoke protein, and a central bridge protein. These
combine to perform one task, ciliary motion, and all of these proteins must
be present for the cilium to function. If the tubulins are absent, then there
are no filaments to slide; if the dynein is missing, then the cilium remains
rigid and motionless; if nexin or the other connecting proteins are missing, then
the axoneme falls apart when the filaments slide.

What we see in the cilium, then, is not just profound complexity, but also irreducible
complexity on the molecular scale. Recall that by "irreducible complexity" we
mean an apparatus that requires several distinct components for the whole to
work. My mousetrap must have a base, hammer, spring, catch, and holding bar, all
working together, in order to function. Similarly, the cilium, as it is constituted, mus
t have the sliding filaments, connecting proteins, and motor proteins for function
to occur. In the absence of any one of those components, the apparatus is useless.

The co
mponents of cilia are single molecules. This means that there are no more
black boxes to invoke; the complexity of the cilium is final, fundamental. And
just as scientists, when they began to learn the complexities of the cell, realized
how silly it was to think that life arose spontaneously in a single step or a
few steps from ocean mud, so too we now realize that the complex cilium can
not be reached in a single step or a few steps. But since the complexity of
the cilium is irreducible, then it can not have functional precursors. Since the
irreducibly complex cilium can not have functional precursors it can not be
produced by natural selection, which requires a continuum of function to work.
Natural selection is powerless when there is no function to select. We can go further
and say that, if the cilium can not be produced by natural selection, then the
cilium was designed.

The Study of "Molecular Evolution"

Other examples of irreducible complexity abound, including aspects of protein
transport, blood clotting, closed circular DNA, electron transport, the bacterial
flagellum, telomeres, photosynthesis, transcription regulation, and much more.
Examples of irreducible complexity can be found on virtually every page of a biochemistry
textbook. But if these things cannot be explained by Darwinian evolution, how
has the scientific community regarded these phenomena of the past forty years?
A good place to look for an answer to that question is in the Journal of Molecular
Evolution. JME is a journal that was begun specifically to deal with the topic of how
evolution occurs on the molecular level. It has high scientific standards, and
is edited by prominent figures in the field. In a recent issue of JME there
?were published eleven articles; of these, all eleven were concerned simply
with the analysis of protein or DNA sequences. None of the papers discussed
detailed models for intermediates in the development of complex biomolecular
structures. In the past ten years JME has published 886 papers. Of these, 95 discussed
the chemical synthesis of molecules thought to be necessary for the origin of
life, 44 proposed mathematical models to improve sequence analysis, 20 concerned
the evolutionary implications of current structures, and 719 were analyses of protein
or polynucleotide sequences. There were zero papers discussing detailed models
for intermediates in the development of complex biomolecular structures. This
is not a peculiarity of JME. No papers are to be found that discuss detailed
models for intermediates in the development of complex biomolecular structures
in the Proceedings of the National Academy of Science, Nature, Science, the Journal
?of Molecular Biology or, to my knowledge, any journal whatsoever.

Sequence comparisons overwhelmingly dominate the literature of molecular evolution.
But sequence comparisons simply can’t account for the development of complex
biochemical systems any more than Darwin’s comparison of simple and complex
eyes told him how vision worked. Thus in this area science is mute. This means
that when we infer that complex biochemical systems were designed, we are contradicting
no experimental result, we are in conflict with no theoretical study. No experiments
needs to be questioned, but the interpretation of all experiments must now be reexamined,
just as the results of experiments that were consistent with a Newtonian view
of the universe had to be reinterpreted when the waveparticle duality of matter
was discerned.

Conclusion

It is often said that science must avoid any conclusions which smack of the
supernatural. But this seems to me to be both bad logic and bad science. Science
is not a game in which arbitrary rules are used to decide what explanations
are to be permitted. Rather, it is an effort to make true statements about physical
reality. It was only about sixty years ago that the expansion of the universe
was first observed. This fact immediately suggested a singular event–that at
some time in the distant past the universe began expanding from an extremely small
size. To many people this inference was loaded with overtones of a supernatural
event–the creation, the beginning of the universe. The prominent physicist
A.S. Eddington probably spoke for many physicists in voicing his disgust with
such a notion 8:

Philosophically, the notion of an abrupt beginning to the present order of Nature
is repugnant to me, as I think it must be to most; and even those who would
welcome a proof of the intervention of a Creator will probably consider that
a single windingup at some remote epoch is not really the kind of relation between
God and his world that brings satisfaction to the mind.

Nonetheless, the Big Bang hypothesis was embraced by physics and over the years
has proven to be a very fruitful paradigm. The point here is that physics followed
the data where it seemed to lead, even though some thought the model gave aid
and comfort to religion. In the present day, as biochemistry multiplies examples
of fantastically complex molecular systems, systems which discourage even an
attempt to explain how they may have arisen, we should take a lesson from physics.
The conclusion of design flows naturally from the data; we should not shrink from
it; we should embrace it and build on it.

In concluding, it is important to realize that we are not inferring design from
what we do not know, but from what we do know. We are not inferring design to
account for a black box, but to account for an open box. A man from a primitive
culture who sees an automobile might guess that it was powered by the wind or
by an antelope hidden under the car, but when he opens up the hood and sees
the engine he immediately realizes that it was designed. In the same way biochemistry
has opened up the cell to examine what makes it run and we see that it, too, was designed.