Progress in Biophysics and Molecular Biology 111 (2013) 92e96

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Progress in Biophysics and Molecular Biology

journal homepage: www.elsevier.com/locate/pbiomolbio

Original research

Rethinking the (im)possible in evolutionq

James A. Shapiro*
Department of Biochemistry and Molecular Biology, University of Chicago, Gordon Center for Integrative Science W123B, Chicago, IL 60637, United States

a r t i c l e i n f o a b s t r a c t

Article history: This paper will discuss the philosophical background to evolutionary theory and present multiple
Available online 14 September 2012 counterfactuals to each of the following seven empirically unsustainable but nonetheless widespread
assumptions about genomic (DNA-based) evolution:
Keywords: 1. “All heredity transmission occurs from parent to progeny”
DNA restructuring 2. “Mutations are the result of inevitable replication errors”
Natural genetic engineering
3. “Mutations occur at constant low probabilities over time” (¼ there are “mutation rates”)
Mobile genetic elements
4. “Virus infection cannot induce genetic changes giving heritable resistance”
Genome evolution
5. “Mutations cannot be targeted within the genome”
6. “Spontaneous hereditary changes are localized and limited to those of small effect”
7. “Cells cannot integrate DNA change with biologically useful adaptive needs”.
The summary take-home lesson is that we have to change from thinking of the genome as a read-only
memory (ROM) that dictates the fate of the cell or organism to conceptualizing the genome as a read-
write (RW) organelle modified transiently or permanently by the cell at different time scales.
Ó 2012 Elsevier Ltd. All rights reserved.

1. Introduction: the philosophical background eventually the entire evolutionary science community insisted
upon randomness at the microscopic level as the basis for macro-
Science inevitably operates in ignorance of future develop- scopic effects (Gissis and Jablonka, 2011).
ments. Results and concepts that seem inconceivable in one period As evolutionary thinking integrated Mendelian genetics into the
become conventional wisdom in later decades and centuries. The neo-Darwinian Modern Synthesis (Huxley, 1942), it adopted the
history of science is replete with examples (Kuhn, 1962). Moreover, mechanistic thinking that prevailed following the intense
it is often the case that we cannot perceive the blinders we impose MechanismeVitalism debate of the early 20th Century. The vital-
on ourselves out of philosophical commitments rather than ists, like Hans Driesch, argued that there must be something special
empirical necessities. about living organisms that informed their activities (Driesch,
Evolutionary thinking began in the 18th Century, at the same 1908). The mechanicists, led by Driesch’s fellow student, Wilhelm
time as other fields in biology were transforming into more Roux, insisted that only demonstrable physical or chemical entities
professional and rigorous disciplines (Stott, 2012). In the second could be invoked to account for biological phenomena (Roux, 1895).
half of the 19th Century, the Darwinian ideas of gradual change and Since the vitalists could not explain the nature of their hypothetical
natural selection as a creative force engaged in a fierce battle with special life force, the mechanists prevailed for the rest of the 20th
religious ideas of divine creation over the explanation of biological Century.
diversity. In order to combat the teleological arguments of William The issues in the MechanismeVitalism debate survive to the
Paley for a divine watchmaker (Paley 1802 (republished 2006)), the present day. In the 1950s, molecular biology and the identification
evolutionists rigorously excluded all notions of goal-oriented of DNA as “the secret of life” were seen as the final triumph of the
activity from their theories. In keeping with 19th Century mathe- mechanists’ physico-chemical view of living organisms. It became
matical thermodynamics, August Weismann (Weismann, 1893) and possible to describe the cell and multicellular organisms in precise
molecular terms. However, the rest of the 20th Century and the
beginning of the 21st Century provided a finely ironic turn to the
philosophical debate.
q Progress in Biophysics and Molecular Biology (2013) March 18e21, 2012, Oxford
As molecular biology advanced, it began to uncover ever more
Workshop on “Conceptual Foundations of Systems Biology”.
* Tel.: þ1 773 702 1625; fax: þ1 773 947 9345. complex and sophisticated multi-molecular networks that carry
E-mail address: jsha@uchicago.edu. out sensory, communication, regulatory and decision-making

0079-6107/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.pbiomolbio.2012.08.016
 J.A. Shapiro / Progress in Biophysics and Molecular Biology 111 (2013) 92e96 93

activities within and between cells (Gerhart and Kirschner, 1997; 6. Evolutionary DNA change occurs rapidly at all genomic levels of
Alberts et al., 2002). At the same time, the 20th Century develop- complexity, from altering a single nucleotide to doubling the
ment of cybernetics, computers and electronic information- entire genome. These rapid changes are often combinatorial in
processing systems began to provide real-world examples of nature and generate novel functionalities, either within a single
capacities the vitalists saw at work in living organisms. The infor- protein molecule, by creating previously non-existent sub-
mation revolution came to biology (Bray, 2009). molecular domains, or by modifying the structure of multi-
This contribution to the workshop attempts to outline how the molecular networks.
biological information revolution and its underlying molecular 7. Cells execute purposeful DNA restructuring events during
observations impact our thinking about evolution. The inten- normal life-cycles in a non-random but also non-deterministic
tionally ambivalent title is there for the following reason. fashion. These goal-oriented natural genetic engineering
Showing how previously excluded (i.e., impossible) notions have processes occur in many organisms, including ourselves. The
been supported by empirical observations inevitably allows us to most integrated and highly regulated natural genetic engi-
consider those same concepts as feasible (i.e., possible) neering processes known occur in the vertebrate immune
hypotheses. system, as it evolves and refines antibody receptors to recog-
nize unpredictable invaders.
2. Lessons we have learned about the sources of hereditary
variation since 1953 3. Seven widely held evolutionary opinions invalidated by
modern observations
Transmissible hereditary changes provide the raw material for
evolution. The elucidation of the structure of DNA made it possible A convenient way to see how much we need to revise our basic
to examine how change arises at the molecular level. The results assumptions about evolutionary change is to look at seven state-
have been revelatory (Shapiro, 2011)1: ments that are widely accepted and generally go unchallenged in
public discourse about evolution. The fact that there are well-
1. Genome change is not the result of stochastic errors but of documented counterfactuals to each indicates how useful a new
biochemical (i.e., cellular) action. set of basic evolution concepts could prove to be.
2. Genome modifications do not arise solely within vertical line-
ages. Genome components from different lineages can be 3.1. All heredity transmission occurs from parent to progeny
combined. The single most important evolutionary change, the
origin of nucleated eukaryotic cells, involved the fusion of at The counterfactuals to this opinion include:
least two different kinds of prokaryotic cells (those lacking
defined nuclei). (a) The susceptibility to all groups of organisms to virus infection,
3. DNA change is a non-random process in the sense that it results incorporation of viral sequences into the genome, and acqui-
from well-defined biochemical operations, each leaving sition of unrelated genome segments by means of viral vectors;
a characteristic signature in DNA structure. Collectively, these (b) the ability of cells from all groups of organisms to incorporate
are called “natural genetic engineering” operators (Shapiro, DNA from the environment into their genomes (http://shapiro.
2011). Cells synthesize, recombine, cut and splice, and other- bsd.uchicago.edu/TableIII.1.shtml);
wise modify their genomes in well-defined reactions. Natural (c) the prevalence of horizontal DNA transfer among prokaryotes,
genetic engineering uses tools such as nucleases, ligases, including endosymbiotic bacteria, and (as we are increasingly
polymerases, reverse transcriptases, recombinases and a wide discovering) among eukaryotes as well as between prokaryotes
variety of mobile genetic elements. and eukaryotes (http://shapiro.bsd.uchicago.edu/TableIII.1.
4. DNA change is non-random in the sense that it is subject to life- shtml);
history regulation. The natural genetic engineering operators (d) the frequent occurrence in life history of symbiogenetic cell
are subject to inhibition and activation by cellular regulatory fusions creating organisms with merged genomes, generally
regimes often epigenetic in nature. Epigenetic regulation separated into two or more specific subcellular compartments
includes RNA-targeted silencing mechanisms in both (Margulis and Sagan, 2002).
prokaryotes and eukaryotes. These regulatory regimes respond
to various sensory inputs in ways that activate natural genetic
engineering when cell or organismal reproduction is chal- 3.2. Mutations are the result of inevitable replication errors
lenged (McClintock, 1984).
5. DNA change is non-random in the sense that natural genetic The counterfactuals to this opinion come in two categories e (i)
engineering events can be targeted within the genome. Tar- cellular capacities to remove errors and (ii) mutational events that
geting occurs by a variety of molecular mechanisms that have involve the action of dedicated natural genetic engineering
distinct specificities: at certain DNA sequences, at certain DNA functions:
structures, or as a result of specific processes, such as replica-
tion or transcription (http://shapiro.bsd.uchicago.edu/TableII. (a) Exonuclease proofreading during DNA replication;
11.shtml). (b) postreplication mismatch repair to remove misincorporations;
(c) introduction of localized “point” mutations by Y class “muta-
tor” polymerases;
1
Almost all the references for the statements that follow are among those posted (d) incorporation of reverse-transcribed RNA sequences into the
online and updated periodically at the website for my book (http://shapiro.bsd. genome;
uchicago.edu/evolution21.shtml) or at special online reference lists prepared for (e) insertion of mobile genetic elements or modules (transposons
this paper. References are principally in the form of links to individual pages and retrotransposons) into new genomic locations (often the
accessible there, where readers can find most citations further linked in clickable
form to the relevant PubMed entry. A file of this paper with clickable links to the
most common source of “spontaneous” mutation);
specialized reference lists can be accessed at http://shapiro.bsd.uchicago.edu/ (f) genome rearrangements, including duplications (Ohno, 1970)
Shapiro.2013.Rethinking_the_(Im)Possible_in_Evolution.html. and further amplifications.
94 J.A. Shapiro / Progress in Biophysics and Molecular Biology 111 (2013) 92e96

3.3. Mutations occur at constant low probabilities over time (¼ bacterial chromosome or to replicating plasmid DNA during
there are “mutation rates”) intercellular transfer;
(d) yeast retrotransposons are targeted by proteineprotein inter-
The counterfactuals to this opinion come from all studies of actions with transcription factors or chromatin proteins to
mutagenesis, which invariably uncover stimuli that make the insert upstream of transcription start sites in euchromatin
observed mutation frequency a function of life history events (Ty1eTy4) or in silent heterochromatin (Ty5);
(http://shapiro.bsd.uchicago.edu/TableII.7.shtml); (e) Drosophila P transposons are “homed” to preferred chromo-
some regions when they contain cis-acting regulatory sites
(a) Treatment with inorganic mutagenic agents, chemicals and active in those regions;
radiation; (f) group II “retrohoming” introns recognize their specific inser-
(b) viral or bacterial infection; tion sites by pairing between nucleotides in the spliced RNA
(c) nutritional or environmental stress; and target DNA;
(d) matings between different populations (“hybrid dysgenesis”) (g) both V region-specific somatic hypermutation and isotype
or interspecific hybridization. switching of heavy chain exons in activated B lymphocytes are
limited to certain transcribed regions and targeted by signals
controlling where transcription occurs.
3.4. Virus infection cannot induce DNA changes giving heritable
resistance
3.6. Spontaneous hereditary changes are localized and limited to
This opinion has long cited the famous 1943 Luria-Delbrück those of small effect
experiment (Luria and Delbrück, 1943) as evidence that viral
infection cannot induce heritable resistance determinants in the This opinion originated with Darwin’s adherence to his geology
infected cells. However, it turns out that such a sweeping conclu- professor Charles Lyell’s Uniformitarian philosophy that long accu-
sion is not valid. Prokaryotes have the CRISPR acquired immunity mulation of gradual changes would result in the major trans-
defense system, and animals can generate so-called “piRNA” formation currently observable (Lyell, 1830). Darwin stated this view
molecules after viral or mobile element infection. Both prokaryotes in his famous quote from Chapter 6 of Origin of Species: “If it could be
and eukaryotes have the capacity to incorporate fragments of demonstrated that any complex organ existed, which could not
genome sequence from invading nucleic acids and use these frag- possibly have been formed by numerous, successive, slight modifi-
ments to generate small RNA molecules that block invader repro- cations, my theory would absolutely break down. But I can find out
duction. As recently as the end of the 20th Century, such adaptive no such case” (Darwin, 1859). Although conventional evolutionists
genomic defense strategies would have been dismissed as incon- acknowledge larger genome changes, they typically treat them as
ceivable. Yet their existence and functions have been incontro- random events of no particular significance for the main lines of
vertibly documented in this century. evolutionary theory. The counterfactuals to this opinion include:

3.5. Mutations cannot be targeted within the genome (a) Protein evolution frequently occurs not by changes in single
amino acids but by “domain shuffling”, the exchange of longer
This opinion is an integral part of the idea that genome change stretches of DNA encoding semi-independent functional
must be a random process. Conventional evolutionists have had to “domains” e a process that involves cutting and splicing DNA
recognize mobile genetic elements and other natural genetic rather than simple replication errors;
engineering systems, but they have held on to the idea of (b) “homeotic” mutations in higher-level genome patterning
randomness by asserting, without empirical support, that change components, such as the animal Hox complexes, have dramatic
cannot be targeted. The truth is quite different, and we know that and extensive effects on the structures of multicellular organ-
multiple well-documented molecular mechanisms of targeting isms; such mutations were studied by proponents of saltational
DNA changes are at work in real time as counterfactuals to this changes in evolution such as Bateson (Bateson, 1894) and
unfounded opinion: Goldschmidt (Goldschmidt, 1933);
(c) episodes where natural genetic engineering has been activated
(a) Many nucleases or transposases target specific DNA sequences by unusual mating or stress frequently results in the occur-
for double-strand breakage to initiate various genome changes, rence of multiple coincident changes to the genome (http://
including homologous recombination in meiosis, mating-type shapiro.bsd.uchicago.edu/TableII.7.shtml);
switching in yeast, VDJ recombination in lymphocytes, and (d) the many examples of whole genome doubling following
insertion of inteins, group I introns, and certain classes of retro- interspecific hybridization in real time or documented to have
transposons (http://shapiro.bsd.uchicago.edu/TableII.11.shtml); occurred at critical transition points in the DNA sequence record.
(b) many viruses insert their genomes into special bacterial chro-
mosome attachment sites by site-specific recombination,
a process that is also used for constructing multiple antibiotic 3.7. Cells cannot integrate DNA change operations with adaptive
resistance determinants (integrons), constructing long multi- needs
coding sequence virulence and other arrays in bacterial
genomes (superintegrons), rearranging DNA to turn genome Part of the determined “materialism” of conventional evolu-
expression on and off (phase variation), removing “intervening tionary theory is the denial that natural genetic engineering oper-
DNA” from protein coding sequences during terminal differ- ations can be integrated with the adaptive needs of the organism
entiation of specialized bacterial cells, and resolving structures experiencing genome change. Once more, this is a philosophical
containing duplications that form in chromosome replication position without empirical support. The counterfactuals include:
and replicative transposition (Hallet and Sherratt, 1997, 2010);
(c) special accessory transposition proteins target the bacterial (a) Germline or other tissue specificity of action by many mobile
Tn7 transposon either to a dedicated “attTn7” site in the genetic elements in animals;
 J.A. Shapiro / Progress in Biophysics and Molecular Biology 111 (2013) 92e96 95

(b) regulation of nuclease action to initiate adaptive processes like “punctuated equilibrium” patterns (Eldredge and Gould, 1972)
meiotic recombination and mating type switching; and the linkage between mass extinctions followed by bursts
(c) coordination of the multiple cleavage, splicing and telomere of origination in the fossil record (Erwin, 2001; Jablonski,
addition events in ciliate protist macronucleus development 2001; Pave et al., 2002).
after sexual exchange;
(d) the various recombination and DNA rearrangement events
underlying microbial phase variation and protein engineering
for immune evasion and modulation of intercellular contacts 5. Functional innovation, not selected optimization of fitness,
(http://shapiro.bsd.uchicago.edu/TableII.5.shtml); is the key problem in evolutionary change
(e) the tightly regulated and highly coordinated natural genetic
engineering processes in lymphocytes that result in antigen Given all the changes introduced into our knowledge of
receptor formation as well as antibody diversification, affinity hereditary variation and evolution by molecular genetics and
maturation, and functional redeployment during the primary genome sequencing, it is time to re-examine our most basic
and secondary immune responses. assumptions about evolution. Ever since Darwin, the mainstream
focus has been on optimizing reproductive success (fitness) by
4. How do we change our thinking? Genomes as readewrite natural selection of random variants.
(RW) memory organelles I have argued in my book (Shapiro, 2011) and online in my
blog (http://www.huffingtonpost.com/james-a-shapiro/) that it
The overarching take-home lesson from all the preceding may be a fundamental misapprehension to think of natural
counterfactuals is that we need to rethink how the genome func- selection as the creative force in evolutionary diversification. By
tions as a cellular memory device (Wilson, 1928). Conventional definition, selection can only operate after change has taken
evolutionary theory treats the genome as the source code for cell place.3 As long as changes were “numerous, successive, slight”
and organism characters e essentially as a read-only memory (Darwin, 1859), it could be argued that the gradual accretion of
(ROM) with no active input and subject to change through copying many changes over long periods of time guided the formation of
errors. The 21st Century alternative view is to treat the genome as evolutionary novelties, like new cell types, adaptive functions,
a readewrite (RW) memory system, more like an iPod than and features of multicellular organisms, like limbs and organs.
a blueprint or even a DVD.2 Decades of study on fitness optimization notwithstanding, we
The active processes of inscribing information onto the RW have now learned about processes that generate rapid genome-
genome are multiple and operate at roughly three different time wide change, like symbiogenesis and hybridizations, and we can
scales: see traces of these events in the genome sequence record. Thus, it
has become necessary to question what biological processes truly
4.1. Within cell cycles, there are transient forms of information constitute the sources of adaptive novelty.
stored in the form of meta-stable nucleoprotein complexes Selection works by testing changed organisms against their
that influence the operation of processes such as replication, unchanged progenitors. Hereditary changes are thus the ultimate
transcription, repair, and cell division. source of novelty. We know that natural genetic engineering is non-
4.2. Over multiple cell cycles, sometimes extending to many random, sensitive to external inputs, and provides all the molecular
organismal generations, the predominant form of inscription is tools necessary for controlling the genome restructuring process.
epigenetic modification of chromatin states. Chromatin Could it be that cell regulation of natural genetic engineering is the
formatting is inheritable at cell division but can also be true source of complex evolutionary innovations that have adaptive
modified in response to stimuli or during cell differentiation. utility? Today we are in a position to ask this question empirically at
Many chromatin states are “imprinted” during gamete the cellular and molecular levels. My guess is that doing so in the
formation; they are reset at each sexual generation and decades to come will prove as eye-opening as the last 60 years of
expression often depends on the gender of the contributing molecular biology.
parent. In microbes, reversible DNA modifications also
contribute to inscriptions heritable for a limited number of cell
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3
The conditions associated with selection can also, of course, influence genome
linked to disruptions of the biosphere. This would explain
variability. We know little about how this influence works aside from its stimula-
tory role (http://shapiro.bsd.uchicago.edu/TableII.7.shtml). Studying the effects of
various stress conditions on the nature of genome modifications is an important
2
Thanks to Perry Marshall for this analogy. topic for 21st Century evolution science.
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