- Point of View
- The future of selection: individuality, the twin legacies of Lamarck & Darwin
-
- Hugo Hoenigsberg
- Departamento de Genética & Evolución
- Universidad Manuela Beltrán
- Bogotá, D.C.
- Colombia
- E-mail: [email protected]
- Genet. Mol. Res. 1 (1): 39-50 (2002)
- Received February 8, 2002
- Published March 6, 2002
Key words: Future selection, Lamarck & Darwin legacies, Evolution, Immune system, Somatic selection
INTRODUCTION
I discuss two modern developments in evolution
that will take part in future studies of selection:
1) The different levels of biological hierarchy - genes,
chromosomes, cells, species and communities - are different survival
entities that require different heritable variations in fitness in
order to function as units of selection in the evolutionary process.
These entities have retained to varying degrees some of their
primordial lower-level identity, where selfish survival of genes was
instrumental to better and multiply their type. That lower-level
unit was natural selection’s milieu. The evolutionary process went
through transitions in the units of selection, from protogenes to
gene networks and to the various biological steps in the hierarchy
of life by inventing cooperation among the lower-level units for the
functioning of the higher-level unit. We argue that the invention of
cooperation among networks of genes was possible through regulation
of the primordial paradigmatic conflictual and selfish program.
Eigen and Schuster (1979) proposed the hypercycle as a way to keep
individual genes from competing among each other so that cooperating
gene groups could emerge. Chromosomes reduce the conflict among
individual genes (Maynard Smith and Szathmáry, 1995). Meiosis
serves to police the selfish tendencies that prevail in the genome
from early programs. Diploidy was an early invention to suppress the
deleterious consequences of selfishness. Uniparental inheritance
of cytoplasm reduces conflict among organelles
through the expression of nuclear or organelle genes (Hoekstra,
1990; Godelle and Reboud, 1995). Finally, other units, like kin
selection, reciprocation, frequent encounters and group structure
regulate conflict in the final transitions from organisms to
societies of cooperating organisms.
2) Weismann´s legacy is that the soma and the
germline are irremediably separated and therefore genetic variation
arising during the course of ontogeny cannot be inherited. In
Weismann´s theory the implication is that the individual is a
unique genetically homogeneous entity. In future studies of
selection evolutionary geneticists will have to recognize that their
past preformistic modes of development (Drosophila, Aves,
Mammals) were biased in their generalizations. Our Professors,
Dobzhansky, Mayr, Simpson, Timofeef-Ressovsky, Buzzati-Traverso and
Rensch were experts in Dipterans and vertebrates. We forgot that
there are other modes of development: somatic embryogenesis,
epigenesis and preformation. If we take all these modes into
consideration we conclude that heritability is controlled by
development, as Weismann recognized. Unicellular organisms can
reproduce clones of themselves with just mitosis, in which all
descendants are capable of giving rise to a new multicellular
individual, while only a fraction of the cells of metazoan zygotes
dividing by mitosis can produce individuals. This is an important
difference, as the former all cells retain totipotency and succeed
in asexually producing a new organism capable of genetic
immortality. On the other hand, only by sequestering a specific cell
lineage can preformistic metazoan development reach gamete formation
and totipotency ...and immortaliy (for a more critical review of
this subject see Buss, 1987).
In somatic embryogenesis a distinct germline is
lacking. Moreover, any cell lineage is capable of both somatic
functions as in a stem cell lineage and reproduction through gamete
formation (e.g., plants). In contrast organisms with epigenetic
development (e.g., annelids, nemertina, echinodermata) possess a
clearly differentiated germline although it appears late after the
primordia of tissues and organs of the adult have developed fully.
The preformistic mode of development has the germline terminally
differentiated in earliest ontogeny, frequently maternally directed
through molecular signals deposited in the egg (e.g., nematodes).
The phyletic distribution of developmental mode
is fairly clear. Somatic embryogenesis is by far the most common
mode of development. Only representatives of the Kingdom Animalia
possess epigenetic and preformistic development. At least nine
animal phyla display somatic embryogenesis throughout their life
cycle. This fact means that it is inaccurate to consider the
individual as the only unit of inheritance in most taxa.
We hope that future studies of selection take
into consideration the fact that plants, colonial invertebrates and
fungi all violate Weismann´s doctrine, displaying enormous
phenotypic plasticity. As we will see later on in this paper
different levels of selection are possible in the Animal Kingdom.
Moreover different strategies have developed in the evolution of
transitions between the unicellular and the multicellular, and these
have emerged according to the presence of individuality in the
various taxa. It is of outmost importance to recognize that the
Modern Synthesis has not generated a terminal theory of ontogeny.
3) The latter part of this essay shows how
Lamarckian inheritance at the molecular genetic level fits in.
WHERE DO ORGANISMS COME FROM?
THE SOLUTION OF CONFLICTS BETWEEN CELLS
Michod’s multilevel selection framework (Michod,
1997a,b, 1999) is an attempt to
answer the dominant feeling in Neo-Darwinian
thinking that organisms are the sole units of selection (Morrell,
1996). Paleontological evidence (Xiao et al., 1998) of the
developmental forms of ancestors of metazoans suggests that the
entire ontogeny of the ancestors of multicellular animals was
probably similar to the type 1 embryogenesis of modern groups
(Davidson et al., 1995).
The different steps in the biological hierarchy -
genes, chromosomes, cells, organisms, kin groups, societies and
communities - undoubtedly have varying degrees of coordination and
cooperation of the different steps that require different
expressions of heritable differences in fitness. This is the same as
saying that each step (or some of them) may function as unit of
selection in the evolutionary process in different ways. No wonder
the study of transition from unicellular to multicellular organisms
has focused on understanding transitions between different levels of
selection (Maynard Smith and Szathmáry, 1995).
The major transitions in evolutionary units that
are relatively easy to identify are individual genes or protogenes
to networks of genes, from the latter to Hydra-like unicellular
organisms, from Hydra-like cells to complex eukaryotic cells with
organelles, and finally to multicellular organisms, species and
societies. These transitions in the ways in which the units of
selection operate, have in common their commitment to cooperation
among the lower level units to jump to the new higher-level unit,
and the control of the conflicting genomes among the lower-level
units where natural selection acts undisturbed. The various
strategies in which the units of selection operate to jump to the
new higher level unit depend on the evolutionary course of
development: in cells like Hydroids heritability is controlled by
development. While in Drosophila the totipotent lineage
undergoes only 13 nuclear divisions per sexual generation, in Hydra
the same lineage may undergo an astronomical number of divisions
before sexuality appears (Buss, 1987). The potential for variation
in Diptera is very low while in Hydra it is enormous. The asexual
reproductive phase of Hydra may be of indeterminate length.
The transition from unicellularity to higher
levels of multicellularity set in much before the phyletic
distribution of development arose. This early transition before
cellular differentiation and the developmental mode responded to
local environmental insults deserves a theoretical treatment.
Eigen and Schuster (1979) proposed the hypercycle
as a means to keep individual genes from competing among themselves
so that cooperating gene networks could emerge. The ability
to identify genes in the cell keeps selfish parasitic genes
from destroying the cooperative nature of the evolving genome.
Chromosomes could be one of the first units to reduce conflict among
the individual genes (Maynard Smith and Szathmáry, 1995). Meiosis
serves to police selfishness of genes and uniparental inheritance
may serve as a means of reducing conflict among organelles by
limiting the expression of either nuclear or cytoplasmic genes (Hoekstra,
1990; Godelle and Reboud, 1995). Moreover, kin selection or group
selection, repeated encounters and group structure may serve to
regulate conflict, or at any rate to control the selfish tendencies
of the lower-level units for the necessary cooperation of genes to
evolve to the higher-level unit of multicellular organisms.
Some have proposed that control of cell behavior
is paramount to reduce conflict among maternal cells (Buss, 1987).
Similarly, Michod (1982) indicates parental control rather than
offspring control in the evolution of altruism. Michod (1999) argues
that "by limiting development to a small number of cell
divisions under the control of maternal cytoplasm, along with
strictly determined cell fate prior to the movement of any cells,
the opportunity for conflict should be reduced".
It is conceivable that the ontogenetic characteristics that
evolved from the ancestors of multicellular life forms are the
result of maternal control and kin selection. This evolution
reduced conflict among cells and promoted
harmonious behavior within the group even at the expense of not
maximizing fitness and adaptation. According to Davidson et al.
(1995), in their developmental regulatory mechanism, the
undifferentiated "set-aside" (stem cells) cells are the
key to more complex structures because of the unlimited replication
of these cells. Following the logic of Davidson, defecting mutation
of undifferentiated stem cells would increase risks for disorders in
the organism because conflict without modifiers would increase, and
pathology, and maybe death, would ensue (Ransick et al., 1996).
For a new level of selection to start it is
important for primitive unicellular life to have solutions to
conflict, and the genetic mechanism for their regulation firmly
established even before cell divisions initiate their movement
toward other cells. Michod (1999) argues that early conflict
regulation can be accomplished by reducing generation time, t, and
by maternal control, and that both can be prevented by stem cells
with unlimited replication potential. Thus, a large population of
set-aside cells can evade conflict modifiers. In order to mediate
conflict and proceed with the evolution of more ontogenic processes
in such a large population of cells, germline modifiers become
necessary. The unit of selection at this point of development is
still the allele that confers better conflict control through the
evolution of the germline and other self-policing modifiers at that
early level.
However, the unit of selection for the adaptation
of modern organisms depends on a step by step developmental process.
In the sea urchin, where the cell types in the adult are determined
after embryogenesis and development of the larva, the unit of
selection of the second process for building the adult form is on
another level (the ancestral type 1 mode of development). Since
cellular conflict can come into play only after type 1 development
is complete, then germline sequestration can be involved and be of
use only when the first rigid-control-conflict has been organized in
toto. Which, by logical deduction, means that the step by step
development of the modern organism has at least two levels of
selection acting in cooperation and in coordination and that the
overall adaptation is the result of the new coherent unit that ends
up at a new level of organization. In other life forms such as in
arthropods, nematodes and chordates there is direct development,
that is, cell types are specified during early cleavage of the
embryo and therefore primitive type 1 development has been avoided
with the concomitant result that primordial specification of the
germline occurs at gastrulation because defecting mutants may arise
quite early and threaten the integrity of the organism. In this kind
of direct development, the organism, at another higher level of
selection, had to have the previous unit well organized at the
intercellular population level in order to reduce the opportunity
for the emergence of within-organism conflicting genomes.
THE CHALLENGE OF THE CONCEPT OF FITNESS
The challenge to the modern evolutionist is how
to conceptualize fitness in the realm of transmission and
heritability so that the units of selection, as they are involved in
a choice, do not turn out to be a poor Neo-Darwinian description of
the actual dynamics involved in the transition from single cells to
multicellular organisms. The hypothesis that the germline and the
self-policing system evolved a progressive adaptation of reducing
and controlling withinorganism change, because this orthoselective
mechanism presumably served to facilitate the transition between
cells and multicellularity, should be seriously considered. Genetic
homogeneity reduces selection. Early germline sequestration would
reduce the opportunity for conflicting genomes and at the same time
would get out of selection’s reach because cells would tend to be
homogeneously cooperative and cell duplication would be limited or
would produce similar cells. Moreover, intracellular or
intercellular mechanisms tending to reduce within-organism change
will be favored not by selection but by the intercellular mechanisms
that promote fusion through cohesion and cooperation as in
Myxobacteria and slime molds. In fact this new mechanism may be
considered an organismic-multicellular-organization, non-Darwinian,
but only while homogenous cooperation lasts or exists to promote a
higher level system (e.g., a tissue, organ, etc.) necessary for
higher-level-system survival. This latter is a more inclusive
evolutionary unit. Clearly, "jumping" to cooperation
through conflicting genome modifiers of various types means reducing
the fitness of lower-level units but at the same time increasing the
fitness of the multicellular "group". There may be moments
between unicellular cooperations and the new higher-level-system in
which multicellular organization has not yet set in, in which case
the evolutionary transition is left without selection of the lower
level or without the higher more inclusive evolutionary unit. There,
we will have "blanks" and no evolution. How long these
"uncertain" periods will last, no one can predict, simply
because they will depend on nature’s circumstances. Since
desertion from cooperative arrangements may result from mutation
among conflict-gene-modifiers, the transition has to wait for the
mechanism of cooperation to initiate the reduction of fitness of
lower level units. Mutation rate and the frequency-dependent
advantages that result within the population of cells have to be at
a minimum and reduced to just some cells, but not all.
Frequency-dependent selection within the population will always
boycott the maximization of group fitness. The transition period
cannot be bountiful in its new fitness function with those
mutation-based frequency-dependent selection individuals. Their
rapid elimination will make way for the higher level unit.
Adaptation as viewed by traditional Neo-Darwinism (although not by
Darwin) (e.g., Williams, 1996) is set to produce only
better-designed individuals (the phenotype) sacrificing the other
levels of organization where conflict mediation made life so
bountiful in many directions.
THE TWIN LEGACIES OF LAMARCK AND DARWIN
The past 45 years have seen an explosion in our
knowledge of basic molecular genetics and this recent revolution is
transforming our view of the mechanisms of inheritance and the
evolution of life on Earth. The time is now ripe to see and analyze
the implications to the basic tenets of evolutionary theory. The
scientific revolution initiated by Charles Darwin, that natural
selection is the driving force in evolution, has become stagnated
with Neo-Darwinian thinking. We believe the dogma requires updating
with the new perspectives of the molecular revolution in the immune
system of animals with backbones, the vertebrates. Therefore, it is
now reasonable to entertain previously heretical concepts and
questions such as: Is there a Lamarckian principle at work in the
immune system? Is Weismann’s Barrier permeable to some extent? In
other words, can some acquired characteristics be inherited? Can we
describe the process in molecular terms?
The key conceptual point is this: mutations in
genes of somatic cells of an animal can possibly be transmitted to
the genes of germ cells and passed on to offspring of future
generations. This is a molecular update to the original idea of the
inheritance of acquired characteristics presented by Lamarck and
later accepted by Darwin in his Pangenesis theory.
We therefore introduce the two, not necessarily incompatible,
concepts: 1) the traditional Neo-Darwinian that evolutionary genetic
variability pre-exists before the selective force acts (natural
selection); versus, 2) the Lamarckian view of the generation of
genetic variability at the same time as the selective force acts.
This latter concept is singularly relevant to the immune system,
where the selective force/environmental stimulus, the infectious
disease, exists at the same time as the appearance of new somatic
genetic variability (the mutated genes encoding antibodies against
infection).
Extra-Nucleic L Systems
Just as it is for the immune system, the modern
Lamarckian molecular process might explain why some species have
been able to undergo an apparent rapid genetic transformation when
sudden environmental changes, or catastrophes have occurred in
nature.
Cluster analysis carried out with 16 ecotypes of
Hydra collected from 15 widely separated and ecologically distinct
localities in India has revealed that local adaptation is simply the
result of switching specific genes, depending on the ecological
requirements (Rastogy and Pandey, 1992). This unicellular animal has
a tremendous regulatory machinery of structural reorganization that
constitutes a challenge to traditional taxonomy (Ewer, 1948;
Grayson, 1971; Campbell, 1983). As with protozoa, Hydra resort to
sexual reproduction only under unfavorable environmental conditions
(Prasad and Mookerjee, 1986). Hydra’s universal adaptation forces
the experimenter to adopt an L system model in view of the fact that
gene frequency changes are not a prerequisite to adaptation. A
single individual can do it with an extranuclear trigger
superadaptability that probably retained the ancestral form of
modern marine larvae that have "type 1" development, which
is a widespread and basic mode of embryogenesis in modern animals.
In type 1 development cleavage begins immediately
after fertilization and proceeds for a number of cell divisions, as
in sea urchin embryos. By the end of cleavage, all the blastomeres
have been specified; the resulting embryo has one thousand cells and
is divided into a group of polyclonal lineages in which each element
gives rise to a certain differentiated cell type. Following
Blackstone and Ellison (1998) one can interpret type 1 development
as a means of reducing the time for development and the
intercellular variability through defecting cells, by way of
maternal control. Maternal control of cell behavior (first proposed
by Buss, 1987) in the transition of unicellular Hydra-like animals
to multicellular ones retaining L type extranucleic inheritance can
be a way of reducing conflict among cells, thereby making
cooperation possible.
Thus, Hydra’s L type superadaptability could be
the origin of multicellular life that went through an evolutionary
transition to a new higher-level unit of individuality.
There have been cases in Drosophila in
which the comparative genetic structure and spatial patterns of
cosmopolitan and local species have shown rapid genetic changes
among profoundly isolated local demes that cannot be interpreted
with the usual Neo-Darwinian theory (Hoenigsberg and Parkash, 1995).
Jenning’s (1940, p. 48) clearly stated that: "The doctrine of
the inheritance of acquired characteristics finds its last refuge in
the genetics of Protozoa. It is a fact that Protozoa are modified in
many ways by the action of environmental conditions, and it is known
that the modified characteristics so induced are inherited for long
periods in vegetative reproduction for hundreds of generations"
(quoted from Sapp, 1987). Moreover, some authors have analyzed epi-
and extranucleic inheritance, and have found it necessary to
postulate Lamarckian inheritance and non-Mendelian inheritance (Landman,
1991; Hoenigsberg, 1992).
The Somatic Selection Hypothesis
The Somatic Selection Hypothesis, first proposed
by Steele (1979), is a modern molecular counterpart of the
Pangenesis idea. This hypothesis proposes a mechanism to explain the
genetic evolution of variable antibody genes (V genes) via a
soma-to-germline gene feedback system. The mechanisms allow for the
creation of new genetic variant animals in response to microbial
invaders from the external environment. There is now no doubt that
the DNA sequences which encode the proteins for the recognition of
foreign invaders (antibodies) undergo rapid somatic gene mutation as
a result of being activated by the antigens of the invading
infectious agent. The most recent data strongly support the theory
that antibody gene mutations are passed back to germline DNA in a
process involving reverse transcription. Reverse transcription,
after a stormy reception, has been accepted after a Nobel Prize was
awarded to Temin and Baltimore (1975) and it has now become widely
recognized as an essential process in the replication of
retroviruses (such as HIV) and other cellular events. Retroviruses
are so-called because genetic information flows from RNA to DNA, the
reverse of the normal direction, DNA to RNA, in all living cells.
For a general summary of the essential points
concerning the immune system as a Lamarckian process in the
Darwinian controversy we offer Rothenfluh and T. Steele (1993);
Rothenfluh and E.J. Steele (1993); Steele et al. (1996, 1998). Most
of the detailed molecular evidence can be found in Rothenfluh et al.
(1995). To analyze Weismann’s barrier we offer Pollard (1984) and
Buss (1987).
The evidence points to the operation of the gene
feedback loop involving the flow of genetic information from somatic
cells (lymphocytes) into the germline genes.
The appearance in the germline of a gene
structure (a specific gene sequence) thought to be present only in
the soma cannot be ignored. Now that the human genome sequencing has
been completed, we would not be surprised if the gene structure
found in the soma is also found in the germline of all vertebrates.
Lamarckian possibilities will have to be admitted as a general
scientific interpretation in biology.
For the variable genes of the immune system one
can say: How do we explain the presence of highly non-random
patterns in the germline V gene DNA which can only arise through
direct antigen-binding selection mechanism acting on the protein
product of the gene (the antibody) instead of the DNA?
Steele’s group at the University of Wollongong
in Australia, ask the question of whether the DNA sequences of
germline V gene benefit in any way from the antigen-driven somatic
mutation and selection events that have occurred in previous
generations. The question is: How many new V region mutant DNA
sequences appear in B lymphocytes during immune responses and are
subject to selection in view of the success of the encoded antibody
in competing for antigen. Steele’s group asks if these new
sequences can pass over the germline DNA (Steele et al., 1998).
The Somatic Selection Theory predicts the
germline transmission of acquired somatic mutations of antibody V
region genes. This stunt could be effected through the enzyme
reverse transcriptase (copying somatic RNA into DNA) mediated by
naturally occurring endogenous RNA retroviruses (lymphocytic ones)
acting as "gene shuttles" which transport mutated V region
gene sequences into germ cells. The next step would be the physical
integration of this somatically derived hereditary information into
the germline DNA so as to replace the pre-existing sequence.
It maybe interesting to remember that in the Proceedings of the
National Academy of Sciences of the United States, Bartl et al.
(1994) speculated that genes could be transmitted between species by
viral infection, thus contributing to the evolution of the
vertebrate immune system. Thus, last century, Weissman’s barrier
was already penetrated. This statement in the prestigious
Proceedings is even more daring than Ted Steele’s idea in the
Somatic Selection Theory.
BACK TO DARWIN AND BEYOND DARWIN INTO LAMARCK
Let us mention a few examples of acquired
characteristics:
Inheritance of Acquired Callousing (Wood Jones,
1943)
Animals such as the ostrich and the African
warthog have large callosities in parts of the body (sternum,
forelimbs, hind limbs) as a consequence of their resting. The strong
horny calluses appear to protect the skin surfaces upon which the
animal kneels. Ostriches rest by squatting on their legs and their
breast-bone (sternum). In these and in other animals, callusing can
also be induced to occur if surfaces are subjected to frequent
rubbing. Therefore, they can be classed as an "acquired"
somatic adaptation. What is particularly interesting is that all
those prominent natural calluses found in ostriches and warthogs are
already well formed in the embryo in the absence of friction or
rubbing. This means that these strategically located callosities are
germline encoded. The skin pads of the soles of the feet of the
newly born humans can be placed in this class.
Traditional Neo-Darwinian explanation (not by
Charles Darwin but by his followers) is that these are peculiarities
of a germline origin brought about by the natural selection process.
Evidently to solve the issue between Neo-Darwinian explanation and
the Lamarckian one requires experimentation with the genes involved.
This is a very difficult and complex phenomenon, certainly more
complex than the antibody V genes of B lymphocytes.
Acquired Inheritance in Bacteria?
Steele and Cairns (1989) and Howard Temin (1989)
reviewed the evidence for the existence of reverse transcriptase
enzymes in bacteria.
Without going into the details, John Cairns and
co-workers of Harvard University were able to produce gene mutations
in bacterial cultures in a directed fashion. They showed that
certain mutations only appeared if chemical substrates related to
the enzyme-encoding genes that mutated were present in the growth
medium. Although controversial, John Cairn’s original explanation
made it necessary to invoke a reverse transcriptase-based gene
feedback loop. Previously Steele (1979) used the same explanation
for his soma to germline theory for the antibody V genes of the
immune system.
Acquired Inheritance in Plants?
What about acquired inheritance in plants where
there is no "Weismann Barrier" separating the soma and the
germline. Acquired somatic modifications in plants which are the
result of somatic mutations can be propagated to progeny when the
seed is formed from that part of the plant that developed the
somatic mutation. Therefore, Lamarckian evolution is and has been a
fact in plants.
Phenomena such as induced heavy metal tolerance
as acquired inheritance have been routinely demonstrated (McClintock, 1978; Cullis,
1984; Pren Das et al., 1990; Rothenfluh, 1995).
Acquired Inheritance in Mice?
This example may not be a so very special scenario because it is
known that mouse sperm cells maturing in the epididymal canals of
the testis have the spontaneous ability to take up exogenous DNA
which can be integrated into the genomic DNA of the sperm nucleus.
Spadafora and colleague’s work (Zoragi and
Spadafora, 1997) has been controversial but now they are defining
many of the steps of the DNA-uptake pathway.
THE IMMUNE SYSTEM
Every day and every minute vertebrates are
subjected to a relentless barrage of potentially invasive pathogenic
viruses and bacteria. How does our immune system fight successfully
such a multitude of pathogens?
Moreover, precisely because of its immense job,
the immune system is far from being at harmony with itself. There is
always the potential for a thorough full-scale "immunological
warfare", in which even intracellular and within tissue immune
responses react to fight off foreign invaders. Health means the
ability to quickly make whole armies of new antibodies to fight
previously unknown pathogens!
Thus, we should remember that we have a very
intelligent system that enables pathogen recognition and regulation
of immune responses, as well as generation and maintenance of
immunological memory. The battle starts during late development of
the embryo. The cells of the system first have to face their own
molecular components ("self antigens"). Shortly after
birth and environmental exposure, the immune system must then adapt
to fight off foreign antigens. The fundamental problem for the
system is being "designed" to fight a vast range of
foreign pathogens, is how do they shun destroying "self".
Another question is, since the molecular surface of the pathogens
cannot be known in advance, how does an animal respond to the
unexpected? And again, how does the system "remember" the
molecular characteristics of previous pathogens so that they can be
fought better at the second or subsequent encounters? And again how
large is the repertoire of antibodies?
Landsteiner’s amazing finding was that he could
elicit antibodies against all of the new chemicals and drugs
produced during the years. These new antigens never existed in
nature! This means that there Neo Darwinian selective pressure could
not exist for antibody production against a substance that did not
exist!
The most mind boggling dilemma is that the
potential repertoire of specific antibodies had to be enormous; and
how can such a system evolve to make antibodies that were not part
of the evolutionary history of the animal? If infectious diseases
have anything to do with the evolutionary development of the modern
immune system, then the molecular surface of the antigens have not
been the driving force. It is more likely that a special biological
strategy emerged to make an immune response to the unexpected.
Even in the cold blooded vertebrates, the fishes,
the immune system of higher warm-blooded vertebrates (birds, mammals
including primates) can be found. All these immune systems have: 1)
an enormous repertoire of antibodies and T cells which facilitate a
response to virtually any antigen; 2) an enhanced (memory) response
to future foreign infections, and 3) the possibility to maintain
self-tolerance.
THE STRUCTURE OF ANTIBODIES
The basic structure of antibodies was first
described during the 1960’s by a group led by Gerald Edelman and
Rodney Porter, who shared a Nobel Prize in 1972.
Briefly, the antigen-binding site is composed of
the complementary folding of the variable region (V) provided by
heavy (H) and light (L) protein chains called an HL heterodimer.
Each antibody molecule has two identical HL heterodimers, except for
pentameric IgM which has 10 HL heterodimers. The constant (C)
regions of the molecule trigger the lysis or phagocytosis of foreign
bacterial cells and particles once the antibody has united its
target antigens.
Conventional genetics says that one gene would be
needed to encode an antibody H chain and that a second gene would be
needed for the L chain. Is there sufficient length of DNA in our
genome to encode millions of antibody specificities? This used to be
a very important question in the sixties, as the Genetic Code was
being deciphered. This question, plus the whole idea of
self-tolerance, forced attention on to what type of strategy the
immune system must employ to generate the diverse repertoire of
antigen-binding receptors necessitated to fight off infectious
diseases. Can the germline strategy, whereby all antibody
specificities are encoded in the egg and sperm cells, be enough to
provide the diverse repertoire of the antigen-binding receptors? Or
does the immune system employ a special somatic strategy in
lymphocytes, in which the genes are mutated or randomly recombined
to generate additional diversity in the repertoire of HL
antibody-combining sites?
Fortunately, the initial scientific battle
resolved itself by the late 1970’s through the molecular genetic
work of immunologist professor Susumu Tonegawa, who was awarded the
Nobel Prize in 1987. Tonegawa’s work turned out to be a mixture of
diversity in the germline genes and diversity in the random somatic
processes (recombination and mutation). Indeed, it turned out that
the essential process for the generation of the enormous diversity
of antibodies and T cell receptors had to be the random somatic
process. That is, during our lifetime our bodies ‘learn’ to
fight numerous invaders and generate many new antibody-coding
sequences within lymphocytes. Now we know that gene sequences from
lymphocytes may be incorporated into germ cells and passed on to the
next generation.
To make a long story short, we now present the
essential elements of the antibody repertoire problem and the
molecular details of the answer. Each antibody heavy chain (H) is a
protein constructed of 400 amino acids (100 for the V region and 300
for the C region) and each light chain (L) consists of about 200
amino acids (100 for the V region and 100 for the C region). Since
each amino acid is specified on translation by a codon of three
bases, this amounts to at least 1800 (600 x 3) bases of DNA sequence
information necessary to encode each antibody HL heterodimer, if
each H and L chain is encoded by a conventional gene. Thus, if there
are one million possible different antibodies, a reasonable
estimate, based upon our current knowledge - this would mean that
the human genome will need to devote almost 2 billion (1800 x
1.000.000 or 1.8 x 109) bases of DNA sequence
information dedicated just to encoding the possible repertoire of
antibodies. If we just restrict the calculation to the essential
encoded information, that is to the critical V regions which
comprise the antigen-binding site of the molecule, this number would
be reduced to about 0.6 x 109, which is about
1/3 of the whole human genome, which has a maximum of 3 billion
bases. In other calculations one would end up with between 1/6 and
1/2 of the DNA sequence space devoted to encoding antibody
molecules, and that would be a logical impossibility.
THE DARWINIAN REVOLUTION
The Darwinian revolution has been a resounding
success in biology since its inception. The problem with great
scientific revolutions is that they frequently become unmovable
dogma. For a while the dogma maybe useful to clarify some points,
but soon an ‘establishment’ form, the individual scientists find
it impossible to break ranks, for their careers and financial
livelihood are put at great risk. This is opposite to Galileo’s
legacy, and yet it is an accurate statement on the human condition.
Today it is an unfortunate fact that
Neo-Darwinian ideas have evolved into almost a religion in certain
quarters, particularly among population geneticists. The New
Lamarckian soma-germline-gene-feedback loops (Steele, 1979
especially) and the extra-nucleic L system inheritance are
passionately resisted. Some embryologists and population geneticists
are still wedded to the neutral theory of molecular evolution of
Kimura (1983). Is it true that the presence of degenerate
third-position ‘silent’ changes within a codon being considered
as evidence for random genetic drift of mutant forms of a gene,
which are selectively neutral, holds water? The very high rate of
‘silent’ base changes in mammalian housekeeping genes (e.g.,
histone genes) certainly indicates powerful natural selection
conserving the function of the protein.
Why discard Steele’s "Somatic Selection
and Adaptive Evolution: On the Inheritance of Acquired
Characters" (1979) or the soma-to-germline concept with its
undoubtedly great explanatory power for the evolution and structure
of the V region gene families of the vertebrate immune system?
The events that are required for the soma-to-germline
theory are: 1) The appearance of the mutation in somatic DNA/RNA, 2)
Its cellular selection by antigens, 3) Its transport to the germ
cells, 4) The copying of RNA into DNA (the copied product is called
cDNA if it comes from reverse transcription, and 5) The physical,
genetic recombination event leading to the integration of the
mutated somatic cDNA copy into germline DNA.
Actually for a long time it has been accepted
that contact between B lymphocytes and foreign antigen produces
large quantities of endogenous harmless retroviruses carrying the
enzyme reverse transcriptase. What the Somatic Selection theory
holds is that the immune response system could be the scenario where
the acquired somatically mutated V sequences in the lymphocytes’
nucleus go back into the germline, thus enriching genetic
variability for future generations; the endogenous retrovirus is the
sophisticated vector mediating genetic communication between soma
and sex cells.
In the Proceedings of the National Academy of
Sciences, USA, S. Bartl, David Baltimore and Irving Weissman (1994)
speculated that genes could be transmitted between species by viral
infection. Barbara McClintock (1978) had informally maintained the
same position many times. Implicit in these speculations is the
penetration of Weissman’s barrier and through it the possible
contribution of the vertebrate immune system.
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