A new process for domesticating animals and plants, the

Genetically Modified Organisms

Antoine Danchin © 2004

唐善安東

This article has been published in Chinese by the journal Science and Technology
in China , 2004

Une discussion en Français a eu lieu à la demande du Sénat de la République

Française sur le sujet

The scene

The Neolithic revolution, 10,000 years ago, is the revolution of agriculture. Since
that time, Man began to domesticate animals and plants. Domestication implies a
man-made selection process that directs evolution of life towards organisms
thought to be useful for us. Implicitely first, then explicitely, we used in this
process our knowledge of heredity to speed up the efficiency of selection. Hence
domestication went to be intimately connected to genetics. Genetics, at the core
of the science of heredity, is based on an alphabetic metaphor. Genetic heredity
is transmitted from generation to generation by a molecule that has the strange
property of behaving as a text, written with an alphabet of four letters. This is
quite different from Chinese writing, and this needs some explanation.

Alphabetic writing uses strings of symbols that are chosen from a narrow list
(usually of the order of 20-30 symbols) and combined sequentially to represent
the phonemes that make spoken words (as in the present sentence, if printed out
in English). As in most languages, there is no link between these letters and the
objects they represent: four (in English), vier (in German), quatre (in French),
τεσσερα (in Greek), 四 (in Chinese) represent the same concept of Number
Theory, number 4 (we see immediately here an important link between alphabets
and numbers: another alphabetic writing, that of numbers, combines ten symbols
to represent the abstract meaning of an integer). Indeed different phonemes, and
hence words, are represented by the infinite combination of letters. Strings of
symbols have many remarkable properties, that will not be discussed here except
to emphasize the fact that, when associated into recursive patterns, they can
make totally unexpected behaviours emerge (see [1] for a general discussion of
this remarkable creative property of strings associated to coding). DNA, the
support of genetic heritage, is made of the chaining of four types of chemicals
(only four), with an order that has something to do with the general functioning of
the cell, the atom of life. In brief, the DNA contained in a cell, its genome, can be
represented as a book of recipe, that tells the cell how to behave in a given
environment (and in particular how to multiply). The rest of the cell behaves as a
kind of computer, that would read (some of) the DNA text (the genetic program)
according to cues provided by the environment. This program is decoded through
a process that can be considered as recursive (briefly, the routine 'make protein'
uses proteins, hence 'make protein' to be put into action). It chains the recipes in
an order that allows the organism to maintain itself, reproduce, react to
environmental cues, protect itself against aggressions, etc. As we shall see, this
precludes total predictability in the case of living organisms, whatever their type,
be they "natural" or "artificial".

All living organisms evolve, and they evolve in a way that cannot, because of the
very way they are constructed, be predicted. To state this in brief, living
organisms are those material systems that have found a way, facing an
unforeseeable future, to create an innovative hence unforeseeable progeny,
among which some will be able to survive in that always unexpected future [1].
The way selection operates is what separates between the natural and the
artificial: natural selection corresponds to all organisms except those that are
domesticated. In the latter case, selection is oriented by the human mind, with
specific characters chosen to be retained or eliminated. Among artificially
selected organisms some have recently undergone a novel selection process,
with direct, rather than indirect, action on their genomes. Those are named
Genetically Modified Organisms (GMOs for short). It is important at this point to
notice that both standard domestication and genetic engineering-based
domestication are artificial processes. The practice of agriculture changes the
environment in a man-driven way, whether it is the result of selection acting
purely on the expressed traits of the organism, the phenotype, or whether it is
gene-based.

A first dramatic change between the old recipes meant to domesticate life and
the science of genetics happened after the discovery of genes by Mendel, De
Vries, Correns, von Tschermak, Morgan, Sturtevant and many others (for
important dates see our compilation). Knowing that the phenotype is mostly
resulting from the combined action of genes, that were apparently organized as
linear sequences and subject to recombination, a first gene-driven approach
resulted in a considerable speed up of the creation of new varieties for
agriculture. This was at the root of the so-called "green revolution". As an
example the weight of an average maize ear doubled between 1970 and 1990.
This is still the most widely used way to domesticate plants and animals, for
example by using statistical means that give marks to phenotypic traits and
connect them to the way genes are organized in the genome (search for
quantitative trait loci, QTLs [2, 3]). Genetic engineering is the most recent step in
this process of gene-driven domestication of plants and animals. Because of
strong socio-political pressure (that cannot be discussed here), it is not (yet)
widely used, except in the USA.

The discovery of the "alphabetic" structure of DNA, coupled to that of restriction

enzymes (enzymes that allow one to play "cut and paste" with DNA sequences)
started an era where the DNA "text" could be knowingly manipulated at the desk,
in silico (for the first definition of that term see [4]), using the familiar cut and
paste procedure of standard word processors, and subsequently manipulated in
vitro, to create artificial genes. In turn these genes could be introduced in vivo in
organisms that were named "Genetically Modified Organisms" to indicate this
fact. Used previously, in vivo recombination was also creating artificial genes, but
in a generally unpredictable way, since it was only at the level of the phenotype
that one could know which gene combination was to be retained. Furthermore, it
was not possible to know exactly what kind of modification of the gene text was
at work. In contrast, in GMOs the modification of the genome is exactly known,
and for this reason it can not only use recombination of genes previously existing
in the parent organisms but also introduce genes from elsewhere or even entirely
artificial genes, in a way that is much wider than that of standard hybridization,
for example.

Perhaps because of that very fact (i.e. introduction of foreign genes into extant
organisms) GMOs (in fact plant GMOs, and, curiously, generally not animal GMOs)
were considered as frightening, or dangerous by the general public. It would be a
research programme in itself to investigate the reasons given by the persons
involved (which of course may be different from the real reasons) and to see
whether this is based on hard facts. We shall not discuss here the political or
economical reasons (which are however, naturally, extremely important) but
restrict our discussion to the following features:

• genomic difference between domestication using GMOs and traditional

domestication

• gene transfer between organisms of the different kingdoms

• gene transfer between domesticated organisms and undomesticated

organisms

• stability of domesticated organisms in the environment

1. Dragons or Chimeras? Hybridization differs between domestication

using GMOs and traditional domestication

The process of selection used by Man was initially to recognize a particular trait
and to try to inbreed organisms that possessed the same trait. Because of the
laws of genetics, this is a very slow process when using the phenotype alone (one
has to wait for many generations to create a really inbred strain, and, for plants,
this is usually requiring one year per generation). However, knowledge of the way
genes are organized, together with molecular means allowing one to connect a
trait with a specific feature of the DNA (restriction enzyme profile, for example)
was used to make better choices in crosses, and this was at the root of the green
revolution, starting just half a century ago [2, 3]. It must be noticed here that the
means employed and still widely accepted as natural by laymen despite their
evident artificial construction, are deeply rooted in molecular genetics (a fact
that, curiously, mass media usually ignore completely). The result was an
enormous increase in yields, both for crops and for animal products, to a point
where the general landscape of the world has been dramatically altered, as
compared to what it was during the last millenium. Another consequence was
that, despite the extraordinary multiplication of Mankind (world-wide, it
quadrupled its number in just one century, China reached 600 million people in
1954), famine has considerably regressed, so much that, when it appears, this is
not due to lack of agro-food resources, but rather to war or other bad political
management.

Human population is still growing and, because this is happening fast, it became
obvious that we were facing a difficult situation if we had to use standard genetic
techniques to keep on increasing agricultural yields. In fact, genetics aside, the
success of the green revolution was mainly caused by a huge consumption in
fertilizers and pesticides, yielding extreme pollution (that is dramatically affecting
wild-life) and energy consumption, considerably increasing our speed in meeting
with global warming. This happened at a time when it became tempting to resort
to directed evolution. Instead of selecting, after the fact, the relevant organisms,
could we create them with the properties we wished them to have? If one would
like to isolate a plant resistant to an insect one could either crossbreed plants (in
an intelligent way) until we find one that resists insects (but this is necessarily a
very slow process because it can only be ajusted by small increments, that each
requires at least two generations to be stabilized) or could we identify genes, the
product of which would kill insects? Such genes could be extracted from any
source, either from plants, animals or even bacteria. This was the basic idea for
the genetic engineering of living organisms.

As can be seen, the main difference with standard genetics are two: first, one can
chose the family of genes of interest; second, one can select not only those
interesting genes from the same family of plants (or related plants) but even from
entirely foreign organisms. This is a considerable extension of an old practice,
hybridization. However, hybrids combine whole genomes, possibly and eventually
creating new species, while in genetic engineering only one gene or a few genes
are introduced in the organism, which certainly does not change its species
nature.

This extension of the hybridization process drove a first line of resistance against
genetic engineering because of a feeling of lack of "purity" of the resulting
modified organisms, a kind of "degeneracy" that is thought to affect the GMOs.
This feeling will deeply depend on the cultures: Dragons are positive in China,
where Chimeras are usually feared in Europe. Of course, many other features are
also important, in particular the fact that, because GMOs are efficient, they are
deeply associated to a culture of profit. Hence a moral question posed by the
public to the people who, at the same time, say that they work for the benefit of
Mankind, but make an enormous profit out of this. To say the least, profit-making
hidden behind a moral smoke screen is obviously questionable. Furthermore,
naturally, the very fact that GMOs "hybridization" is a deep extension of an old
common practice, makes it clear that its consequences have not yet been fully
explored. It is therefore quite understandable that this practice rose a heated
debate. Rather than enter its details (this would ask for a long book) we shall now
dwell on a series of questions raised by the existence of GMOs, questions which
can mostly be answered in a fairly clear fashion. However to my view these
(misleading) questions, although placed in the limelight, are not the most
important questions one should ask about the creation and use of GMOs. We shall
say a few words about that in the conclusion of this article.

2. Gene transfer between organisms of the different kingdoms

When people discuss the impact of GMOs they usually assume the existence of
gene transfer between GMOs domestic plants and wild plants. What evidence do
we possess about the ubiquity of gene transfer in the living kingdoms? A few
references will tell. We have tried in this article to bring attention to some work
that is usually not taken into account in review articles or books dealing with
horizontal transfer of genes (which, as a matter of fact, are often stemming from
medical work, especially dealing with nosocomial infections [5, 6]).

Although it has been recognized for a long time that horizontal gene transfer
could occur in Bacteria, the importance of the phenomenon has only been
evaluated recently, with the knowledge of the first complete genomes. In this
process, it is important to recognize first the amount of DNA that can be
considered as horizontally transferred, as well as the processes permitting the
transfer to occur. In particular, it should be understood that, at the present time,
we possess only indirect evidence of a widespread process, and, in particular we
have almost no evidence for its importance when one considers transfer between
the three domains of life, Bacteria and Archaea (usually single cell organisms,
without a nucleus) and Eukarya (organisms with cells containing a nucleus, as
plants and animals do). It should also be stressed that in general (except for the
direct transfer between microbes), the time course of the processes investigated
is of the order of one event per million years, or even tens of millions of years.
Another important fact has to be taken into account: cells with a nucleus
(Eukarya) have a variety of organelles derived from Bacteria that lived inside
them (mitochondria, chloloplasts and the like). These symbionts slowly
transferred most of their genes to the nucleus of their host. Despite this
extraordinarily closed environment, it took probably one billion years to transfer
many of the bacterial symbiont genes into the nucleus of the host. This shows
that, even when organisms are in close association, stable gene transfer is a very
rare event. To understand the processes requires to know something not only
about the mechanisms for transfer, but also something about the selective forces
that permit its stabilization.

Horizontal transfer between Bacteria is linked to the existence of specific viruses,

the bacteriophages, and to bacterial sexuality. It can also directly involve DNA
through the process of transformation. Infection by bacteriophages that became
cryptic when integrated in their host's genome (the process called lysogeny) has
been recognized by Félix d'Hérelle as early as 1917. Conjugation and sex in
bacteria have been recognized by Elie Wollman and François Jacob in the fifties.
Both processes, that transfer genes in the wild, were used to transfer genes from
homologous organisms in the laboratory since the beginning of the molecular
biology era. However the extent of horizontal transfer of genes into chromosomes
was really appreciated only in 1991 when Médigue et al., comparing the
difference in codon usage in Escherichia coli, proposed that a whole class of
genes (now known to comprise 15% of the genes in E. coli K12) bore the
signature of horizontal transfer [7]. Nothing, however, could be said about their
origin, except that, in most cases, these genes appeared to have been
transferred through a conjugation process (and hence came from other bacteria),
and, in a minor set of genes through phage lysogeny [8]. It is now widely
accepted that there is significant gene transfer between Bacteria (and even
between Bacteria and Archaea [9]) but the extent of that transfer is subject to
intense debate [10]. In general it appears that horizontal transfer is strongly
linked to the existence of persisting unusual environmental conditions (stress
conditions). Persistence of the transferred genes requires repeated selection
pressure. This can be achieved by co-evolution of genes of the receiver organism,
in which case the foreign gene is definitively incorporated into the host genome.
In this respect it should be noted that the evidence accumulated so far is highly
biased by the choice of genes relevant to one or another interest of the
investigator. In reality, what is relevant for selection is only a gene in context, i.e.
genomic context and environmental context. This can be perceived in the fact
that, when there is horizontal transfer, several genes are in general transferred
together (e.g. "pathogenicity islands"). It has been published that organisms such
as bacteria belonging to the Bacillus cereus family can have enormous
coordinated acquisition of foreign DNA, while they keep constant the core of their
genome (with concomitant conserved general phenotype) [11]. This is prominent
even in highly transferable vectors, such as plasmids, transposons and the like. It
is therefore somewhat irrelevant to argue about the transfer of isolated genes, if
one has to make a reasonable risk assessment: the context of the gene is as
important as the gene itself. In this respect the widely spread existence of
plasmids seems to be a way to keep a genome as intact as possible, while
keeping means to obtain foreign genes for some time, when they permit coping
with special environmental conditions.
It should be noticed that although Gram negative bacteria are generally better
equipped than their Gram positive counterparts (in particular because
conjugation is much more frequent in their case), the efficiency of gene
expression is good only in Gram-/Gram- exchanges or Gram+/Gram- exchanges,
and not in the Gram-/Gram+ direction. This is most probably due to the fact that
many Gram+ organism do not possess a ribosomal S1 protein [12]. As a
consequence, it is always much easier to express foreign genes in Gram negative
bacteria than in Gram positive bacteria. This fact should be taken into account
when considering the stability of a gene transfer (and also when considering
heterologous gene expression for industrial purposes!).

A general state of the art in the investigation of gene transfer from plants to
bacteria shows that in this particular direction this is an extremely rare event, if it
exists at all [13]. For a long time it was assumed that one possessed one example
of an enzyme present in bacteria, copper superoxide dismutase, that came from
an animal host. However recent evidence argues very strongly to the contrary
[14, 15].The idea at that time was that the photoluminescent bacteria that were
found in the gut of the swordfish had acquired their copper SOD gene from their
host by horizontal transfer, since only manganese and iron SODs were known to
be present in bacteria at that time. Recently the subject took a renewed interest
however, when it was found that copper SOD could be involved in pathogenesis,
and that it was in fact widespread among Gram negative bacteria [16-18]. It
becomes therefore difficult at this point to separate between horizontal transfer
and divergent evolution. A similar type of study suggested that bacterial
catalases may have been acquired by horizontal transfer from a fungus species
[19]. Data have accumulated for a long time for other genes, in particular genes
involved in the synthesis of antibiotics to suggest their propagation by horizontal
transfer. Here the selection pressure seems important: indeed those organisms
that make certain antibiotics have to be immune to them, and therefore should
either differ in their general metabolism, or synthesise genes of resistance. In the
case of penicillins and the related cephalosporins, having been discovered, as
everybody knows, in a fungus, it was interesting to study the possibility of their
biosynthesis (and resistance) in bacteria. Most rest on non-ribosomal protein
synthesis, a process that may be of very ancient origin. Other enzymes, involved
in the synthesis and degradation of metabolites specific to eukaryotes, have been
found in bacteria [20]. The hypothesis of horizontal transfer stems from the fact
that the product not being made in bacteria, it is difficult to see how divergent
evolution could have maintained its similarity to an eukaryotic counterpart. It is
clear from these studies that, if the transfer occurred, this happened during
extremely long periods of time, and often very early during evolution (in
particular at a time when oxygen started to be a major pollutant of the Earth [21,
22]). To our knowledge, there is no widespread evidence for recent and efficient
direct gene transfer from eukaryotes to prokaryotes (see the review by Nielsen et
al, [13]), except in man-made experiments (cloning and heterologous expression
of eukaryotic genes in bacteria is of course an obvious case in point). It is
interesting to note that implicit perception of this biological fact may have been
at the source of much resistance against genetic engineering at its onset, in the
mid 1970s.

The main difficulty for this process to occur in a natural environment is not the
DNA transfer per se, but the expression of the eukaryotic genes in bacteria (in
particular in Gram positive bacteria). Indeed, separation of the compartments for
transcription and translation in eukaryotes resulted in a specific way to initiate
translation, without the signals that are required in prokaryotes (ribosome binding
sites in particular). In addition most eukaryotic genes are interrupted by introns.
This means that functional transfer would occur only with genes copied from their
mRNA template, through the action of a reverse transcriptase. The fact that it can
be performed in the laboratory shows nevertheless that it is in principle a
possible, although extremely unlikely, event. The fact that only very rare traces of
this event can be found in extant organisms suggests that, unless there is a
strong and specific selection pressure, there is no maintenance of the transferred
gene in the bacteria where it occurred. Furthermore there is strong accumulating
evidence that most proteins do not diffuse freely in the cytoplasm of the cells, but
are part of multiprotein complexes. This means that the presence of a foreign
gene will be more a burden than a help. Because the organisation of prokaryotes
and eukaryotes is so different, this may explain why the gene transfer from these
widely different domains of life is exceptional: there is no selective advantage to
have developped an efficient means of gene transfer, if the gene products cannot
be easily functional after transfer. In brief, transfer from eukaryotes to
prokaryotes is an extremely rare event despite the widespread existence of DNA
in nature [23].

Transfer from Bacteria to Eukarya is probably much more frequent, in part due to
symbiosis of bacteria that became mitochondria and chloroplasts (of course the
transformation plasmids of Agrobacterium sp. have also a role, but much smaller
than real symbiosis). This natural process was exploited as the first way to
produce plant GMOs. Indeed some bacteria have a specific systems meant to
transfer genes to plants [24]. Curiously, despite this ubiquitous systems, leading
to plant tumors, there is apparently no large invasion of plants by bacterial genes
(except, once again, for those that were present when the genes from
endosymbiotic bacteria and cyanobacteria led to the formation of mitochondria
and chloroplasts). Despite the fact that it is widespread, there is not much
indication that bacterial genes (antibiotic synthesis genes, for example) have
invaded the plant kingdom. This probably reflects an intrinsic way of the various
kingdoms to protect themselves against foreign genes, a phenomenon which has
an obvious implication in resistance to viruses, for example.

At this point of our reflection, we have alluded to many processes that permit
gene transfer, such as conjugation, viral infection, DNA transformation,
retrotransposition and similar phenomena. It is interesting to review briefly their
existence in nature. It seems remarkable that, instead of metabolic genes, all
kinds of retro-elements have repeatedly invaded genomes. This is the case for
example of the extremely widespread Mariner element, discovered as a major
invador by Hugh Robertson [25-27]. This element has invaded many animal
genomes (including primates, at least twice), leaving related organisms free from
it. But it should be noticed that, although invasion is frequent, this is of course to
be considered at the geological time-scale (for example the invasion of the
primate lineage occurred twice, the last time being some 10-30 millions years
ago...). The important observation linked to this element is that it may transport
with it adjacent genes and therefore greatly contribute to gene transfer. It is also
important (but this has been performed only in laboratory experiments) to
recognize that this element can work in bacteria [28]. Finally, group I introns (and
group II introns [29]) are also major indicators of horizontal transfer. But there is a
controversy about their origin and the time of their transfer between genomes. In
particular it is still not resolved why, although typical eukaryotic markers, they
have been found in bacteriophages such as E. coli T-even bacteriophage T4 and
B. subtilis bacteriophages [30-32].

3. Gene transfer between domesticated organisms and undomesticated

organisms

Domestication of plants and animals used genetics as soon as this science

became available. Before that, domestication was a very slow process [33], with
much outbreeding between domesticated organisms and their wild type parents.
However, although genes can in principle move freely in either direction, it does
not seem to have an important impact. If this were so, domesticated organisms
would have invaded the planet in the absence of Man action, and this is not the
case. Triggered by profit-making journals, an extremely heated controversy exists
in the case of maize, where it has been suggested that genes from GMOs spread
into the environment [34]. However this is far from being proven, and, even if it
were proven, the impact is extremely low [35]. In any case, the general impact of
modern agriculture is enormous. This impact however is not due to gene flow, but
to practices that eliminates wild organisms and uses fertilizers, purposedly
replacing wild plants and animals by domestic ones, which makes specific
assessment of the further possible role of GMOs difficult to perform. There is an
immense literature of sayings about gene flow, but not much measurements
supporting any important transfer: hunting practices and uprooting plants is by
far, the most efficient way to replace wild genes by domesticated genes. In fact,
experimental work in the domain is scarce, but one can find studies indicating
that domestication led to hybridization with a sustained flow from domesticated
plants to wild plants, in the case of weeds [36, 37]. This is the most obvious
situation for such a process to happen, since the only way for weeds to escape
human action is to mimick, as much as possible, the phenotype of cultivated
plants. However no study tells how far from cultivated fields this type of transfer
can be observed. General observation in forests of the lack of similarity between
the ancestors of cultivated trees and their present varieties argues against the
idea that domesticated trees could easily survive in the wild. Knowledge of
genome sequences will, in the near future, help us to resolve this issue in a non
controversial way.

4. Stability of domesticated organisms in the environment

Domestication is 10,000 years old. Initially, starting with wild animals and plants,
cross-breeding must have been extremely frequent: this is extremely well
illustrated in perhaps the case of the oldest domesticated animal, the dog [38].
Hence a significant gene flow between domesticated and wild organisms took
place during the whole of the Neolithic. However, as domestication proceeded,
the selected traits were less and less adapted to wild life, and, when deprived of
specific selection pressure, the gene flow reduced to an extremely low level. This
explains why ancestors of present day domesticated grasses, for example, are
still extant [39]. As a matter of fact, present day cultivated plants or domestic
animals cannot survive in the wild. Most problems caused by biological invasions
are due to wild-type animals or plants that conquer new biotopes, either because
of present global warming, pollution, or accidental introduction (this is in
particular the case in islands, which were until recently remaining isolated, or
continents such as Australia, where invasion by European plants and animals has
dramatic consequences [40-44]). Domestication of living organisms results in
enhancement of specific traits that fit the usage Man wishes to do with them. This
is quite visible in races of horse that vary between animals bred for competion, to
animals bred for heavy work (this is disappearing with mechanisation) and
animals bred for meat. The same apply to cattle with even more specialization,
animals being bred either for meat or for milk. They also can be selected to
survive in specific ecological niches (such as mountains for example). The main
danger facing these animals (or plants) is not mixing up with wild species, nor
particular danger towards Man, but, rather to disappear because of lack of
financial interest for breeders, while they represent a very important gene pool
selected through centuries or even millenia of hard work. Conservation of
domestic animals and plants genetic resources is a major challenge, that can only
be met with special germ-line banks and/or association with specific ways to
improve revenues of the breeders [45].

Provisional conclusion and caveat: is life predictable?

All this might tell us that GMOs do not pose any problem. In fact, I wish to end
this article by a caveat (that applies to any type of man-driven selection,
standard domestication included), to stress that, because life is in essence
unpredictable, we should never say that we know what will be the outcome of any
of our actions in the domain. The central concept often named the Central Dogma
of Molecular Biology, is that "information transfer", always associated with two
processes essential for life, metabolism and compartimentalization, rests on two
laws. The first one is complementarity, which to a sequence of primordial
motifs associates a complementary sequence of motifs (chain of letters) that
results in exact and complete specification of the former. The second law is
coding, which uses a cipher allowing the rewriting of the DNA text symbolized by
a four letter alphabet into a second text symbolized by a twenty letter alphabet.
Molecular biology used to rely on the alphabetic description of the genes. It is
now further exploring the metaphor, in which the genome is understood as
providing the complete text of the recipe allowing the construction, the
development, the survival and the evolution of any living organism. Let us stress
again that it would be a deep mistake to mix up the book of recipe with the meal,
as journalists do when they try to make the public believe that the knowledge of
the Human Genome sequence will allow us to cure all diseases! What this
metaphor, which comprizes an alphabetic text and a coding process, accounts for
is the possibility of a true creation (i.e. sudden appearance of an entity which
cannot be predicted from what was existing before, but only accounted for a
posteriori in the chain of evolution), as repeatedly witnessed when analyzing the
evolution of species. Comparing genomes allows one to tell those places where
creation operates: the Darwinian trio Variation / Selection / Amplification makes
material systems evolve, evolution creates new functions, which, to come to
being, recruit preexisting structures (hence the "tinkering" features stressed by
François Jacob). And hence the impossibility of predicting a function from the
structure alone [46]. Naturally, because any creation is unforeseeable, one will
only be able to explain a posteriori how this or that recruitment allowed the
development of that particular function. It is there that we begin to construct the
means to explore, from what we know of the past, what might be conditions for
new creation to come, as well as the places where it will be possible (this is a
central question, for example, when one wishes to understand how and where
new diseases can emerge). The alphabetic metaphor of the genetic program is so
appropriate that one can represent the cell and its program as a computer and its
program. That particular computer would have the particularity, in the program it
deciphers and modifies, to provide the appropriate instructions not only for its
own duplication, but for the duplication of the machine itself. The most
elementary machine of this type, as proposed by Alan Turing, is made of a
read/write head, of a mobile "tape" which passes through the head and which
carries only a linear sequence of symbols, and of a mechanical device which
allows the tape to go forward, go backward, stop, or read the symbols in the
band, as a function of the previous readings by the head. This machine is
essentially defined by the fact that it allows formal separation between the
machine proper (the read/write head and the mechanics needed to make the
tape move), the data which set the conditions under which the program is
executed, and the program itself. The major conceptual question asked by this
metaphor is whether one is allowed to separate the program from the machine.
As I argued elsewhere [1], the experiments which are at the root of the molecular
techniques of biotechnology provide us with a first indication that this separation
is effective. It is demonstrated in an illuminating way in these experiments of cell
cloning that have been so fashionable since 1997. For a living organism the
genetic program leads to the real construction of the machine. The logic needed
for an effective complementarity between matter and its symbolic representation
has long been discussed by von Neumann in the mid-sixties [47]. It requires some
"jump" from matter to abstractness. If the program is a model for a universal
construction rule that plans the duplication of both its own description and that of
the machine, then the duplication of the program together with that of the
machine becomes logically possible. But this requires that the machine and its
symbolic representation (program in the program) be somehow separated. Thus
there is a need, in addition to the genetic program, for the existence, somewhere,
of an image of the machine. This is still an open question, that must be answered
if we wish to pursue the consequences of the alphabetic metaphor.

If this metaphor is appropriate, then we have to accept its deepest

consequences. And they are that, in principle, it will never be possible to predict
exactly what will be the concrete outcome of a given genetic program. Of course
when things are kept very similar to one another they must more or less behave
in the same way, but very minute differences, such as those that separate dogs
from wolves, can have enormous consequences [48]. We should always bear this
in mind when considering our practices involving living organisms.

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