Physiology is rocking the foundations of evolutionary biology
Denis Noble
Department of Physiology, Anatomy & Genetics,
Sherrington Building, Parks Road, Oxford, OX1 3PT UK
Denis.noble@dpag.ox.ac.uk
Abstract
The “Modern Synthesis” (Neo-Darwinism) is a mid-twentieth century gene-centric view of evolution, based on random mutations accumulating to produce gradual change through natural selection. Any role of physiological function in influencing genetic inheritance was excluded. The organism became a mere carrier of the real objects of selection: its genes. We now know that genetic change is far from random and often not gradual. Molecular genetics and genome sequencing have deconstructed this unnecessarily restrictive view of evolution in a way that reintroduces physiological function and interactions with the environment as factors influencing the speed and nature of inherited change.
Acquired characteristics can be inherited, and in a few but growing number of cases that inheritancehas now been shown to be robust for many generations. The twenty-first century can look forward to a new synthesis that will reintegrate physiology with evolutionary biology.
Keywords Evolutionary theory, evolutionary biology, Modern Synthesis, Central Dogma, epigenetic inheritance, Lamarckism, transposons.
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Introduction
As 2012 came to a close, an article appeared in the Proceedings of the National Academy of Sciences
with a title that would have been inconceivable in such a prestigious journal just 5-10 years ago.
“Rocking the foundations of molecular genetics” (Mattick 2012) is a commentary on a groundbreaking
original experimental article (Nelson, Heaney et al. 2012) in the same issue of the journal
showing epigenetic maternal inheritance over several generations. My title echoes that of Mattick, but
it also goes further. It is not only the standard twentieth century views of molecular genetics that are
in question. Evolutionary theory itself is already in a state of flux (Jablonka and Lamb 2005; Noble
2006; Beurton, Falk et al. 2008; Pigliucci and Müller 2010; Gissis and Jablonka 2011; Noble 2011;
Shapiro 2011). In this article, I will show that all the central assumptions of the Modern Synthesis
(often also called Neo-Darwinism) have been disproven. Moreover, they have been disproven in ways
that raise the tantalising prospect of a totally new synthesis: one that would allow a re-integration of
physiological science with evolutionary biology. It is hard to think of a more fundamental change for
physiology, and for the conceptual foundations of biology in general (Melham, Bard et al. 2013). The
Modern Synthesis (Fisher 1930; Huxley 1942; Mayr 1982) attributed genetic change solely to chance
events, about which physiology could say very little. The germ line was thought to be isolated from
any influence by the rest of the organism and its response to the environment, an idea that was
encapsulated in the Weismann barrier (Weismann 1893). Note that this was animal-specific and did
not apply to other life-forms. But if acquired changes can be inherited through many generations, then
physiology becomes relevant again since it is precisely the study of function, and functional changes.
These are what determine epigenetic processes.
I start with some definitions. I will use the term ‘modern synthesis’ rather than ‘Neo-Darwinism’.
Darwin was far from being a Neo-Darwinist (Dover 2000; Midgley 2010), so I think it would be
better to drop his name for that idea. As Mayr (1964) points out, there are as many as 12 references to
the inheritance of acquired characteristics in The Origin of Species (Darwin 1859) and in the first
edition he explicitly states ‘I am convinced that natural selection has been the main, but not the
exclusive means of modification’, a statement he reiterated with increased force in the 1872, 6th
edition. In some respects, my article returns to a more nuanced, less dogmatic, view of evolutionary
theory (see also Müller 2007; Mesoudi, Blanchet et al. 2013), which is much more in keeping with the
spirit of Darwin’s own ideas than is the Neo-Darwinist view.
Summary of the Modern Synthesis
The central assumptions of the Modern Synthesis that are relevant to this article are fourfold (see also
the summary in Koonin 2011).
First, genetic change is random. Interpreted in modern terms as referring to DNA, the changes can be
thought of as restricted to single step changes in one (or a very few) bases brought about, e.g. by
copying errors, radiation or any other random event. The concept of a purely random event is not easy
to define. The physico-chemical nature of biological molecules will, in any case, ensure that some
changes are more likely to happen than others. Randomness cannot therefore be defined
independently of asking ‘random with respect to what’? I will use the definition that the changes are assumed to be random with respect to physiological function and could not therefore be influenced by
such function or by functional changes in response to the environment. This is the assumption that
excludes the phenotype from in any way influencing or guiding genetic change.
Second, genetic change is gradual. Since random events are best thought of as arising from
microscopic stochasticity, it will generally be the case that many such events would have to
accumulate to generate a major change in genome and phenotype. Of course, there are point mutations
that can have a dramatic effect on the phenotype, but these are rare. The prediction would be that the
evolution of gene sequences, and the amino acid sequences of the proteins formed should not occur in
ways that would require large domains to move around within and between genomes.
Third, following genetic change, natural selection leads to particular gene variants (alleles) increasing
in frequency within the population. Those variants are said to confer an advantage in terms of fitness
on the individuals concerned, which therefore increasingly dominate the population. By this process,
and other mechanisms including genetic drift and geographic isolation, new species can arise.
Fourth, the impossibility of the inheritance of acquired characteristics. This is the main thrust of the
synthesis and it is the means by which Darwin’s ideas were represented as distinct from those of
Lamarck (1994 , originally published 1809). This assumption also excludes any notion of what
Lamarck called ‘le pouvoir de la vie’, a life-force that could in some way be seen as directing
evolution through increasing complexity or through adaptation. Lamarckism was excluded not only
by the experiments of Weismann (1893) but also by the central dogma of molecular biology (Crick
1970). Both claim that the genetic material is isolated from the organism and its environment; ‘sealed
off from the outside world’, to use The Selfish Gene popularisation of the idea (Dawkins 1976, 2006).
All these assumptions have been disproven in various ways and to varying degrees, and it is also
important to note that a substantial proportion of the experimental work that has revealed these breaks
has come from within molecular biology itself. Molecular biology can now be seen to have
systematically deconstructed its own dogmas (Shapiro 2009; 2011).
Are mutations random?
“It is difficult (if not impossible) to find a genome change operator that is truly random in its action
within the DNA of the cell where it works. All careful studies of mutagenesis find statistically
significant non-random patterns of change, and genome sequence studies confirm distinct biases in
location of different mobile genetic elements” (Shapiro 2011, p 82). Shapiro gives large numbers of
references on the non-random nature of mutations. As already noted, though, the key question is not
so much whether changes are truly random (there can be no such thing independent of context) but
whether they are chance events from the viewpoint of function. The evidence is that both the speed
and the location of genome change can be influenced functionally. Changes in the speed of change are
well-known already from the way in which genome change occurs in immunological processes. The
germ line has only a finite amount of DNA. To react to many different antigens, lymphocytes ‘evolve’
quickly to generate extensive antigen-binding variability. There can be as many as 1012 different
antibody specificities in the mammalian immune system and the detailed mechanisms for achieving
this have been known for many years. The mechanism is directed since the binding of the antigen to
the antibody itself activates the proliferation process. Antigen activation of B cell proliferation acts as
a selective force. The targeting of the genomic changes, which maintains the functional structure of
the antibody while diversifying antigen recognition, occurs by protein-DNA binding specificity (VDJ joining (Shapiro 2011, p 173)), coupling to transcription signals (somatic hypermutation), and
lymphokine-directed transcription of heavy chain switch regions (Class Switch Recombination)
(Shapiro 2011, pp 66-69).
Similar targeted genomic changes occur outside the context of the immune system. The reader is
referred to table II.7 (Shapiro 2011, pp70-74)1 for many examples of the stimuli that have been shown
to activate this kind of ‘natural’ genetic engineering, while table II.11 from the same book (pp. 84-
86)2 documents the regions of the genomes targeted. 32 examples are given. One example will suffice
to illustrate this. P element homing in fruit flies involves DNA transposons that insert into the genome
in a functionally significant way, according to the added DNA. There is up to 50% greater insertion
into regions of the genome that are related functionally to DNA segments included within the P
element. Thus “Insertion of a binding sequence for the transcriptional regulator Engrailed targets a
large fraction of insertions to chromosomal regions where Engrailed is known to function.” (Shapiro
2011, p 83). A possible explanation is that the donor element and the target site may be brought close
together in the nucleus, i.e. organisation of the genome is important. This kind of information is also
therefore ‘genetic’. We should not limit the concept of a ‘gene’ and the description ‘genetic’ to
protein-template regions of the genome, particularly since we now know that 80% of the non-protein
regions are transcribed, 20% with known function, 60% not yet known.3 It was clearly premature to
label this DNA as ‘junk’. Structural organisation also represents information that is transmitted down
the generations. DNA is not just a one-dimensional sequence. It is a highly complex physiological
system that is regulated by the cell, tissues and organs of the body. This will become even clearer in
the next section.
Is genetic change gradual?
It was the Nobel Prize-winner Barbara McClintock who introduced the idea that the genome is ‘an
organ of the cell’ (McClintock 1984). She won her prize for physiology or medicine in 1983 over 40
years after she had made the ground-breaking discovery of chromosome transposition (now called
mobile genetic elements). She worked on maize, and early reactions to her work were so sceptical that
she stopped publishing her research in 1953 (Keller 1983). The consequences for evolutionary theory
were also ignored since the phenomenon was not thought to occur in animals. We now know that
animal genomes are full of transposons. About 3500 of the estimated 26,000 human protein-template
regions contain exons originating from mobile elements (Shapiro 2011, p 109). This contrasts with a
much lower number, 1200, in mice, even though the number of protein template regions is similar in
both genomes. This suggests that transposons may have played a major role in primate and human
evolution. Over two-thirds of the human genome is derived from mobile elements (de Koning, Gu et
al. 2011), and there have been well over 3 million transposition events in its evolution.
McClintock could not have anticipated the evidence that would later emerge from whole genome
sequencing studies in various species, but it fully vindicates the general and widespread significance
of her discovery. The Nature 2001 report (International Human Genome Mapping Consortium 2001)
compared protein-template regions for several classes of proteins from yeast, nematode worms,
drosophila, mice and humans. In the case of transcription factors (Figure 45 of the Nature report) and
chromatin-binding proteins (Figure 42 of the Nature report) the evidence shows that whole domains
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1 http://shapiro.bsd.uchicago.edu/TableII.7.shtml
2 http://shapiro.bsd.uchicago.edu/TableII.11.shtml
3 http://www.genome.gov/10005107 http://genome.ucsc.edu/ENCODE/
up to hundreds of amino acids in length have been amplified and shifted around among different
genetic loci in the genome. Of course, the sequencings were done on the contemporary species. We do
not therefore know precisely when in the evolutionary process the transpositions may have occurred.
However, a number of the domains and combinations are restricted to certain lineages. And of course,
gradual changes also occurred within the sequences. The experimental evidence on genome
sequencing shows multiple ways in which evolutionary change has occurred. Note also that domain
shuffling and the polyphyletic origins of genomes were established facts well before the full
sequencing of genomes (Gordon 1999; Shapiro 2011).
The mechanisms of transposable elements illustrate one of the important breaks with the central
dogma of molecular biology. Retrotransposons are DNA sequences that are first copied as RNA
sequences, which are then inserted back into a different part of the genome using reverse transcriptase.
DNA transposons may use a cut and paste mechanism that does not require a RNA intermediate. As
Beurton et al.(2008) comment, “it seems that a cell’s enzymes are capable of actively manipulating
DNA to do this or that. A genome consists largely of semi-stable genetic elements that may be
rearranged or even moved around in the genome thus modifying the information content of DNA.”
The central dogma of the 1950s, as a general principle of biology, has therefore been progressively
undermined until it has become useless as support for the Modern Synthesis (Werner 2005; Mattick
2007; Shapiro 2009) or indeed as an accurate description of what happens in cells. As Mattick (2012)
says, “the belief that the soma and germ line do not communicate is patently incorrect.”
An important point to note is the functionally significant way in which this communication can occur.
In bacteria, starvation can increase the targeted transposon-mediated reorganisations by five orders of
magnitude, i.e. by a factor of over 100,000 (Shapiro 2011, p 74).
Mobile transposable elements that have been involved in evolution come in more forms than just
retrotransposons and DNA transposons. They include the movement and/or fusion of whole genomes
between species. Symbiogenesis is the mechanism by which eukaryotes developed from prokaryotes,
with mitochondria and chloroplasts being the most well-known examples, having originated as
bacteria that invaded (or were engulfed by) the ‘parent’ cell (Margulis 1981; Brown and Doolittle
1997; Margulis and Sagan 2003). During evolution some of the acquired DNA transferred to the
nucleus. Horizontal transfer of DNA is ubiquitous in the prokaryote world, but also far from absent
amongst eukaryotes (Shapiro 2011). Other forms of mobile DNA include plasmids, viruses and group
2 introns, which are all prokaryotic elements. To these we can add group I introns and inteins
(Raghavan and Minnick 2009), multiple classes of transposons (Curcio and Derbyshire 2003),
multiple classes of retrotransposons (Volff and Brosius 2007), and various forms of genomic DNA
derived from reverse transcription (Baertsch, Diekhans et al. 2008). One of the major developments of
Darwin’s concept of a ‘tree of life’ is that the analogy should be more that of a ‘network of life’
(Doolittle 1999; Woese and Goldenfeld 2009). As with other breaks from the Modern Synthesis, that
synthesis emerges as just part of the evolutionary story.
The inheritance of acquired characteristics
In 1998, the great contributor to the development of the Modern Synthesis, John Maynard Smith,
made a very significant and even prophetic admission when he wrote “it [Lamarckism] is not so
obviously false as is sometimes made out” (Maynard Smith 1998), a statement that is all the more
important from being made by someone working within the Modern Synthesis framework. The time was long overdue for such an acknowledgement. Nearly 60 years ago Waddington had written
“Lamarck is the only major figure in the history of biology whose name has become to all extents and
purposes, a term of abuse. Most scientists' contributions are fated to be outgrown, but very few
authors have written works which, two centuries later, are still rejected with an indignation so intense
that the skeptic may suspect something akin to an uneasy conscience. In point of fact, Lamarck has, I
think, been somewhat unfairly judged.” (Waddington 1954)
So why, given his extraordinary (but completely correct) admission, did Maynard Smith not revise his
view of the mechanisms of evolution? The reason he gave in 1999 was that “it is hard to conceive of a
mechanism whereby it could occur; this is a problem” (Maynard Smith 1999). At that time, the
examples of the inheritance of acquired characteristics could be counted on the fingers of one hand.
They included Waddington’s work on genetic assimilation (Waddington 1959) and Sonneborn’s work
on the inheritance of non-genetic changes in paramecium membrane-cilia orientation (Sonneborn
1970). The flow of papers during the last five years showing non-mendelian inheritance is, however,
now becoming a flood of evidence. Sadly, Maynard Smith is no longer with us to comment on this
important development. Let us try though to look at the evidence through his eyes, because although
he saw a problem, he also added that it was “not I think insuperable” (Maynard Smith 1999).
The examples he had in 1998 were not only few and relatively old. They were also fairly easy to
assimilate into the Modern Synthesis or ignore as special cases. Waddington’s work could be
dismissed since it was not certain that no mutations were involved, although this would be very
unlikely on the time scale of his experiments. Any variation that was necessary was almost certainly
already present in the gene pool. His work on fruit flies essentially consisted in selecting for certain
combinations of existing DNA sequences in the population gene pool by selective breeding from flies
with unusual phenotypes induced by treating embryos with heat or ether (Bard 2008). He was the first
to call this mechanism ‘epigenetics’ (i.e. over and above genetics), but he did not mean the specific
form that we now understand by that term, i.e. the marking of chromatin to change the patterns of
expression.
The Modern Synthesists should not have dismissed Waddington’s experiments, for example as simply
“a special case of the evolution of phenotypic plasticity” (Arthur 2010). Of course, the Modern
Synthesis can account for the inheritance of the potential for plasticity, but what it cannot allow is the
inheritance of a specific acquired form of that plasticity. Waddington’s experiments demonstrate
precisely inheritance of specific forms of acquired characteristics, as he claimed himself in the title of
his paper (Waddington 1942). After all, the pattern of the genome is as much inherited as its
individual components, and those patterns can be determined by the environment.
But I can see why Modern Synthesists thought the way they did: giving up such a central tenet of the
Synthesis would have been difficult anyway, not least because of the extraordinary distinction of the
twentieth century biologists who developed it. We are talking, after all, of Julian Huxley, Sewell
Wright, J B S Haldane, R A Fisher, George Price, Bill Hamilton, just to name a few. Waddington’s
genetic assimilation process was discounted as a break with the Modern Synthesis precisely because it
did not involve gradual accumulations of mutations and was not viewed as a challenge to that process.
But that is to put the question the wrong way round. It is precisely whether gradual mutations form the
only mechanism that is in question. Waddington’s work was a proven alternative additional
mechanism. Even 70 years ago, the Modern Synthesis could have been admitted to be incomplete.
In a different way, Sonneborn’s work was brushed aside as being on a unicellular organism, with no
separate germ line. The Modern Synthesis has always had a strongly zoological basis, tending to ignore prokaryotes, unicellular organisms, and plants, even though these cover more than 80% of the
whole duration of the evolutionary process long before ‘zoology’ could even have a meaning in
evolutionary history.
But the evidence for the inheritance of acquired characteristics has now moved right into the
zoological domain. All the remaining examples I shall quote here are on multicellular organisms,
including mammals, and they refer to pioneering work done in the last 7 years.
Anway et al (Anway, Leathers et al. 2006; Anway, Memon et al. 2006) demonstrated that an
endocrine disruptor vinclozolin (an anti-androgenic compound), can induce transgenerational disease
states or abnormalities which are inherited for at least four generations in rats. The transmission is via
epigenetic modifications carried by the male germ line and may involve either marking of the genome
or transmission of RNAs. More recent work from the same laboratory has shown that the third
generation granulosa cells carry a transgenerational effect on the transcriptome and epigenome
through differential DNA methylation (Nilsson, Larsen et al. 2012). The sperm nucleus contains much
more than the genome (Johnson, Lalancette et al. 2011).
An alternative approach to determining how the organism as a whole may influence the genome and
whether such influences can be transmitted transgenerationally is to study cross-species clones, e.g.
by inserting the nucleus of one species into the fertilised but enucleated egg cell of another species.
Following the gene-centric view of the Modern Synthesis, the result should be an organism
determined by the species from which the genome was taken. In the great majority of cases, this does
not happen. Incompatibility between the egg cytoplasm and the transferred nuclear genome usually
results in development freezing or completely failing at an early stage. That fact already tells us how
important the egg cell expression patterns are. The genome does not succeed in completely dictating
development regardless of the cytoplasmic state. Moreover, in the only case where this process has
resulted in a full adult, the results also do not support the prediction. Sun et al (Sun, Chen et al. 2005)
performed this experiment using the nucleus of a carp inserted into the fertilised but enucleated egg
cell of a goldfish. The adult has some of the characteristics of the goldfish. In particular, the number
of vertebrae is closer to that of the goldfish than to that of a carp. This result echoes a much earlier
experiment of McLaren and Michie who showed an influence of the maternal uterine environment on
the number of tail vertebrae in transplanted mice embryos (McLaren and Michie 1958). Many
maternal effects have subsequently been observed, and non-genomic transmission of disease risk has
been firmly established (Gluckman and Hanson 2004; Gluckman, Hanson et al. 2007). A study done
in Scandinavia clearly shows the transgenerational effect of food availability to human grandparents
influencing the longevity of grandchildren (Pembrey, Bygren et al. 2006; Kaati, Bygren et al. 2007).
Epigenetic effects can even be transmitted independently of the germ line. Weaver et al showed this
phenomenon in rat colonies where stroking and licking behaviour by adults towards their young
results in epigenetic marking of the relevant genes in the hippocampus that predispose the young to
showing the same behaviour when they become adults (Weaver, Cervoni et al. 2004; Weaver 2009). 4
Molecular mechanisms
The results I have described so far establish the existence of transgenerational non-mendelian
inheritance. This section describes recent studies that demonstrate the molecular biological
mechanisms and that the transmission can be robust for many generations.
___________________________________
4 This field is growing so rapidly that there is not space in this review to cover it. A more extensive bibliography can be found at http://shapiro.bsd.uchicago.edu/Transgenerational_Epigenetic_Effects.html
Rechavi et al worked on C. elegans and the non-mendelian inheritance of the worm’s response to viral
infection (Rechavi, Minevish et al. 2011). This is achieved by the infection inducing the formation of
an RNA silencer. They crossed worms with this response with worms that do not have it and followed
the generations until they obtained worms that did not have the DNA required to produce the
silencing RNA but which nevertheless had inherited the acquired resistance. The mechanism is that
transmission of RNA occurs through the germ line, and is then amplified by using RNA polymerase.
The inheritance of the acquired characteristic is robust for over 100 generations.
The work of Nelson et al (Nelson, Heaney et al. 2012) that stimulated Mattick’s article in PNAS with
which I began this review is from the laboratory of Joe Nadeau at the Institute of Systems Biology in
Seattle. Their article begins by noting that many environmental agents and genetic variants can induce
heritable epigenetic changes that affect phenotypic variation and disease risk in many species.
Moreover, these effects persist for many generations and are as strong as conventional genetic
inheritance (Richards 2006; Jirtle and Skinner 2007; Youngson and Whitelaw 2008; Cuzin and
Rassoulzadegan 2010; Nelson and Nadeau 2010; Guerrero-Bosagna and Skinner 2012). The challenge
now is to understand their molecular basis. The experiments of Nelson et al were on the Deadend1
(Dnd1) gene which enhances susceptibility to testicular germ cell tumors (TGCTs) in mice, in part by
interacting epigenetically with other TGCT modifier genes in previous generations. They showed that
genetically engineered deficiency of Apobec1 modifies susceptibility, either alone or in combination
with Dnd1, and either in a conventional or a transgenerational manner. The heritable epigenetic
changes persisted for multiple generations and were fully reversed after consecutive crosses through
the alternative germ-lineage. The Apobec family is an unusual protein family of cytidine deaminases
that can insert mutations in DNA and RNA (Conticello 2008).
A further example of a molecular mechanism is that of paramutation, which consists in the interaction
between two alleles at a single locus. This can induce permanent epigenetic changes in organisms
from maize to mice (Chandler 2007; Cuzin, Grandjean et al. 2008; Sidorenko, Dorweiler et al. 2009;
Arteaga-Vazquez, Sidorenko et al. 2010; Chandler 2010; Erhard and Hollick 2011).
These examples of robust inheritance of acquired characteristics reveal a wide array of mechanisms
by which such inheritance can be achieved. Nature seems to work through the cracks, as it were, of
the gene-centric view. Those cracks have now been discovered to be great fissures through which
functionally significant inherited changes occur. Such mechanisms could not have been foreseen at
the time when the Modern Synthesis was formulated, or even just a decade ago. To Maynard Smith’s
(1999) comment (“it is hard to conceive of a mechanism whereby it could occur”) the reply must be
that some of those mechanisms have now been found and they are robust.
In addition to establishing the molecular mechanisms, these experiments help to explain an otherwise
puzzling finding. Conventional genetic inheritance often accounts for less than 10% of observed
inherited risk. Similar conclusions have been drawn from genome-wide association studies (GWAS)
and from studies on identical twins (Roberts, Vogelstein et al. 2012). This observation, in itself,
creates problems for the gene-centric view, and it is now clear that non-Mendelian inheritance may
provide a large part of the explanation (Slatkin 2009).
So what went wrong in the mid-twentieth century that led us astray for so long? The answer is that all
the way from the Weismann barrier experiments in 1893 (which were very crude experiments indeed)
through to the formulation of the central dogma of molecular biology in 1970, too much was claimed
for the relevant experimental results, and it was claimed too dogmatically. Demonstrating, as
Weismann did, that cutting the tails off many generations of mice does not result in tail-less mice
shows, indeed, that this particular induced characteristic is not inherited, but it obviously could not
exclude other mechanisms. The mechanisms found recently are far more subtle. Similarly, the
demonstration that protein sequences do not form a template for DNA sequences should never have
been interpreted to mean that information cannot pass from the organism to its genome. Barbara
McClintock deservedly gets the last laugh: the genome is indeed an ‘organ of the cell’.
Towards a new synthesis between physiology and evolutionary biology?
This review has been written for a primarily physiological audience, but its implications are profound
for biological science in general. It shows that, through recent discoveries on the inheritance of
acquired characteristics, the analysis of physiological function can be important to the mechanisms of
evolutionary change. The full extent of this feedback from function to inheritance remains to be
assessed, but it can’t be doubted that it runs counter to the spirit of the Modern Synthesis. The
challenge now is how to construct a new Synthesis to take account of this development. In the table
below I call this the Integrative Synthesis. I believe that in the future, the Modern Synthesis, and the
elegant mathematics that it gave rise to, for example in the various forms and developments of the
Price equation, will be seen as just one of the processes involved, a special case under certain
circumstances, just as Newtonian mechanics remains as a special case in the theory of relativity. The
mathematics of evolutionary theory is developing to take additional processes into account (e.g.
Bonduriansky and Day 2009; Slatkin 2009; Nowak, Tarnita et al. 2010). In many cases, that is already
implicit, for example where the ‘gene’ is really an inherited phenotype regardless of the mechanism of
inheritance. Where the mechanism matters, e.g. in allowing blending rather than discrete inheritance,
the mathematics will be interestingly different. There are also important implications for the rate of
evolutionary change since an adaptive characteristic may be acquired by many individuals
simultaneously, thus avoiding the slow process of a chance mutation in an individual spreading
through the population.
A central feature of the Integrative Synthesis is a radical revision of the concept of causality in
biology. A priori there is no privileged level of causation. This is the principle that I have called the
theory of biological relativity (Noble 2008; 2012). As Werner puts it, “all levels have an equal
contributing value” (Werner 2003). Control is therefore distributed, some of which is inherited
independently of DNA sequences. The revision of the concept will also recognise the different forms
of causality. DNA sequences are best viewed as passive causes since they are only used when the
relevant sequences are activated. DNA on its own does nothing. The active causes lie within the
control networks of the cells, tissues and organs of the body.
Conclusions
We are privileged to live at a time of a major change in the conceptual foundations of biology. That
change is set to bring the physiological study of function right back into centre stage. It is worth
quoting the relevant paragraph from Mattick’s commentary on the Nelson et al work:
“The available evidence not only suggests an intimate interplay between genetic and
epigenetic inheritance, but also that this interplay may involve communication between
the soma and the germline. This idea contravenes the so-called Weismann barrier,
sometimes referred to as Biology’s Second Law, which is based on flimsy evidence and a
desire to distance Darwinian evolution from Lamarckian inheritance at the time of the
Modern Evolutionary Synthesis. However, the belief that the soma and germline do not
communicate is patently incorrect.”
The only parts of this statement that I would change are, first, to remind readers, as I noted earlier in
this article, that Darwin himself did not exclude the inheritance of acquired characteristics. Second, to
remind us that Lamarck himself did not invent ‘Lamarckism’ (Noble 2010). As we move on beyond
the unnecessary restrictions of the Modern Synthesis we move back towards a more genuinely
‘Darwinian’ viewpoint, and we also move towards a long-overdue rehabilitation of Lamarck. Of
course, neither Darwinism nor Lamarckism remains unchanged. Neither could have anticipated the
work of the 21st century. But we can now see the Modern Synthesis as too restrictive and that it
dominated biological science for far too long. Perhaps the elegant mathematics and the extraordinary
reputation of the scientists involved blinded us to what now seems obvious: the organism should
never have been relegated to the role of mere carrier of its genes.
Acknowledgements This article is based on lectures given in New Delhi, India, in December 2011 (http://www.appicon2011.org/ ), Suzhou, China, in November 2012 (http://www.voicesfromoxford.org/video/physiology-and-the-revolution-in-evolutionary-biology/184 ), the Rupert Riedl lecture at the University of Vienna (http://medienportal.univie.ac.at/uniview/veranstaltungen/detailansicht/artikel/rupertriedl-lecture-the-music-of-life/ ) in March 2013, and the forthcoming President’s Lecture at the IUPS Congress in the UK in July 2013
(http://www.iups2013.org/ ). I would like to thank Jonathan Bard, Nicholas Beale, Richard Boyd, Georges Christé, Dario DiFrancesco, Malcolm Gordon, Gerhard Müller, Raymond Noble, David Paterson, Etienne Roux, James Shapiro, Ania Sher, Eric Werner and Michael Yudkin for valuable discussions, some of whom gave specific feedback on this article. Further relevant reading can be found in twofocussed issues of Progress in Biophysics and Molecular Biology: see (Melham, Bard et al. 2013; Sharma 2013)
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Isn't that interesting -- bilaterians "evolved the genetic capacity for spectacular diversity," for no apparent reason, long before it was "expressed." The Science paper notes "an apparent > 100-million-year gap between the evolutionary innovation and its consequences"! For all that time, the "genetic capacity" sat on its hands, doing nothing. Then, thanks to sheer dumb luck, it turned out that the "innovation" was exactly what was necessary to evolve into all the diverse forms of animals we observe. The only thing missing was an environmental trigger.
