Bibliography of Supplementary Resources For Science Instruction

Various
Discovery Institute
January 1, 2004

NOTE: On Monday, 11 March 2002, Stephen Meyer and Jonathan Wells of the Discovery Institute submitted the following Bibliography of Supplementary Resources to the Ohio State Board of Education. These 44 scientific publications represent important lines of evidence and puzzles that any theory of evolution must confront, and that science teachers and students should be allowed to discuss when studying evolution. The publications are not presented either as support for the theory of intelligent design, or as indicating that the authors cited doubt evolution. Discovery Institute has made every effort to ensure that the annotated summaries accurately reflect the central arguments of the publications.

The following scientific articles, papers, and monographs are drawn from leading journals in the respective disciplines represented: e.g., Cell (for molecular biology), Nature and Science (for general science), Trends in Ecology and Evolution and Annual Review of Ecology and Systematics (for evolutionary biology), or from prominent university presses (e.g., Cambridge University Press). The publications represent dissenting viewpoints that challenge one or another aspect of neo-Darwinism (the prevailing theory of evolution taught in biology textbooks), discuss problems that evolutionary theory faces, or suggest important new lines of evidence that biology must consider when explaining origins.

Over half of the papers listed below were published within the past 2-3 years, with the remainder published throughout the 1990s. The resources are organized in three broad categories: (a) Questions of Pattern, (b) Questions of Process, and (c) Questions about the Central Issue: the Origin and Nature of Biological Complexity. "Pattern" concerns the large-scale geometry of biological history: how are organisms related to each other, and how do we know that? "Process" concerns the mechanisms of evolution, and open problems in that area. Lastly, "Biological Complexity" concerns the origin of what makes organisms distinctively what they are: the source of the specified complexity of biological information.

Questions of Pattern

1. Ying Cao, Axel Janke, Peter J. Waddell, Michael Westerman, Osamu Takenaka, Shigenori Murata, Norihiro Okada, Svante Pääbo, and Masami Hasegawa, "Conflict Among Individual Mitochondrial Proteins in Resolving the Phylogeny of Eutherian Orders," Journal of Molecular Evolution 47 (1998): 307-322.

It is widely believed that molecular data confirm morphological data when the history of groups such as the mammals is being reconstructed. Many cases exist, however, where molecules (such as proteins) give "false" or erroneous phylogenies. This paper, by a team of researchers from Japan, Germany, and Australia, demonstrates that different mitochondrial proteins can give different, and contradictory, groupings. In particular, the protein NADH dehydrogenase (ND1) places primates and rodents together as closest relatives, with ferungulates (artiodactyls + cetaceans + perisodactyls + carnivores) as more distantly related to primates -- in contradiction to most other data, which places primates and ferungulates together as closest relatives. The authors conclude that this anomalous phylogenetic grouping "is not due to a stochastic error, but is due to convergent or parallel evolution" (p. 321), suggesting that molecular evidence is not free from the confounding (historically misleading) effects known to plague other types of systematic data, such as anatomical patterns.

2. Simon Conway Morris, "Evolution: Bringing Molecules into the Fold," Cell 100 (2000):1-11.

In this article, Conway Morris (a paleontologist and professor in the Department of Earth Science, Cambridge University) argues that "when discussing organic evolution the only point of agreement seems to be 'It happened.' Thereafter, there is little consensus, which at first sight must seem rather odd." Conway Morris goes on however to stress that "our understanding of evolutionary processes and mechanisms is incomplete" (p. 1), and "constructing phylogenies [evolutionary histories] is central to the evolutionary enterprise, yet rival schemes are often strongly contradictory. Can we yet recover the true history of life?" (p. 1). He concludes his review of current problems in evolutionary biology with a provocative thesis:

...if evolution is in some sense channeled, then this reopens the controversial prospect of a teleology; that is, the process is underpinned by a purpose. It is no coincidence that interest in the Anthropic Principle, which broadly seeks evidence for the boundary conditions of the Big Bang and the ensuing physics and chemistry uniquely favoring the emergence of life...is being extended to the fields of biochemistry and molecular biology (for one view, see Denton, 1998)

The book Conway Morris cites here -- by the New Zealand geneticist Michael Denton -- is entitled Nature's Destiny: How the Laws of Biology Reveal Purpose in the Universe.

3. W. Ford Doolittle, "Tempo, Mode, the Progenote, and the Universal Root," in W. Fitch and F. Ayala, eds., Tempo and Mode in Evolution (Washington, DC: National Academy Press, 1995), pp. 3-24.

4. W. Ford Doolittle, "At the core of the Archaea," Proceedings of the National Academy of Sciences USA 93 (1996): 8797-8799.

5. W. Ford Doolittle, "Uprooting the Tree of Life," Scientific American, February 2000, pp. 90-95.

6. W. Ford Doolittle, "Phylogenetic Classification and the Universal Tree," Science 284 (1999):2124-2128.

7. W. Ford Doolittle, "The nature of the universal ancestor and the evolution of the proteome," Current Opinion in Structural Biology 10 (2000):355-358.

A professor in the Department of Biochemistry and Molecular Biology of Dalhousie University (Canada), W. Ford Doolittle is one of the world's leading molecular evolutionists. In these three related articles (the Scientific American piece is aimed at a general audience), Doolittle argues that recent discoveries in molecular biology have begun to fracture the root of Darwin's single Tree of Life. "Thus, there is no more reason to imagine only a single first kind of cell as the progenitor of all contemporary life," he argues (p. 356 of the Current Opinion article), "than there is to imagine only Adam and Eve as progenitors of the human species." Doolittle contends that biology must rethink Darwin's single Tree:

Some biologists find these notions confusing and discouraging. It is as if we have failed at the task that Darwin set for us: delineating the unique structure of the tree of life. But in fact, our science is working as it should. An attractive hypothesis or model (the single tree) suggested experiments, in this case the collection of gene sequences and their analysis with the methods of molecular phylogeny. The data show the model to be too simple. Now new hypotheses, having final forms we cannot yet guess, are called for. (p. 95, Scientific American article)

8. Douglas H. Erwin, "Early introduction of major morphological innovations," Acta Palaeontologica Polonica 38 (1994): 281-294.

Is the puzzle of the Cambrian Explosion -- the geologically sudden appearance of the major animal body plans -- merely an artifact of taxonomic methods, a consequence of retrospectively classifying disparate groups that, at their origin, were not distinct? Douglas Erwin, a paleontologist at the Smithsonian Institution, says no. He argues that "the primary problem is the generation of the novel morphologies accorded high rank" -- forms as distinctive as arthropods, mollusks, and chordates -- "not higher taxa per se. ... The asymmetric pattern of morphological innovation [exhibited in the Cambrian Explosion] would be with us even if systematists eliminated ranks entirely" (p. 282, 284). In other words, the arthropod body plan by any other name would be as strange if it appeared suddenly in the Cambrian, as do actual arthropods. Given that the problem of the Cambrian Explosion is real, asks Erwin, how are we to solve it? In this article, he reviews several competing (albeit not necessarily exclusive) theories: empty ecospace (the idea that the animals radiated because they could, "ecospace" -- i.e., specific niches -- stood open and waiting to be occupied); genetic hypotheses, such as elevated mutation rates and novel genetic mechanisms; developmental hypotheses, which postulated that rapid morphological change was driven by the "discovery" of novel cell types and ontogenetic architectures; and lastly, complexity models, which regard initial bursts of innovation, followed by stabilization, "as an expected consequence of complex systems" (p. 289). Erwin does not decide in favor of any of these hypotheses, noting that although future work may alleviate the problem of testing, tests cannot "be conducted with much confidence today because of uncertainties in metazoan [animal] phylogeny" (p. 291).

9. Trisha Gura, "Bones, molecules...or both?" Nature 406 (2000):230-233.

This article from Nature, one of the top two science journals in the world (the other being Science), explores the conflicts that arise in biological systematics -- the science that deals with the large-scale relationships of organisms -- between anatomical lines of evidence, such as skeletal data, and newer sources of evidence, such as DNA or proteins: the molecular data:

When biologists talk of the "evolution wars", they usually mean the ongoing battle for supremacy in American schoolrooms between Darwinists and their creationist opponents. But the phrase could also be applied to a debate that is raging within systematics. On one side stand traditionalists who have built evolutionary trees from decades of work on species' morphological characteristics. On the other lie molecular systematists, who are convinced that comparisons of DNA and other biological molecules are the best way to unravel the secrets of evolutionary history. (p. 230)

Science writer Gura explains how molecules and morphology in evolutionary systematics are frequently in conflict, giving different histories for groups of organisms, and the attempts that are being made to sort out the contradictions.

10. Michael S. Y. Lee, "Molecular Clock Calibrations and Metazoan Divergence Dates," Journal of Molecular Evolution 49 (1999): 385-391.

Laypeople (and scientists from other fields) often assume that evolutionary biologists have successfully dated the historical divergence points of species using molecular data -- and that such dates provide evidentially independent confirmation of evolutionary hypotheses. The so-called "molecular clock" thus conveys an aura of analytic precision in phylogenetic estimation. In this paper, however, Michael Lee (a molecular evolutionist at the University of Queensland, Australia) explains that molecular clocks in fact rest on paleontological assumptions for calibration, and thus that their reliability can be no better than the fossil data (and hypotheses) that they employ. As he explains,

Molecular clocks need to be calibrated, and this can be done only by direct recourse to (hopefully reliable) dates in the fossil record. Calibration of clocks indirectly through use of dates inferred from other molecular clock studies (which in turn are ultimately based on the fossil record) is less desirable, as it adds an extra layer of uncertainty, especially if these molecular inferences are highly controversial. (p. 386)

Reviewing several molecular clock studies, Lee is troubled that only a single fossil calibration point is used, and yet "it appears that none of these molecular studies have critically examined the reliability of this fossil dating by consulting the primary palaeontological literature, which is surprising in light of their conclusions that the fossil record is liable to be very misleading" (p. 386). In summary, Lee urges great caution in putting much weight on molecular clocks, given their reliance on palaeontological calibration:

Even if one makes the bold assumption that molecular clock models have little error, there seems little objective reason for accepting as sacrosanct a few fossil dates used in calibrations and rejecting as unreliable the much more numerous fossil dates that contradict the resultant molecular estimates. ... Unfortunately, molecular clock studies have yet to provide a set of rigorous criteria for justifying which fossil dates are to be used in calibrations and which are to be treated with skepticism. (p. 389)

11. Michael S. Y. Lee, "Molecular phylogenies become functional," Trends in Ecology and Evolution 14 (1999): 177-178.

It has been widely believed that "molecular convergence" is impossible: i.e., that gene and protein sequences could not evolve to the same sequence via natural selection. While morphological patterns may exhibit misleading functional similarities -- misleading, that is, because the similarity in question would exist not for historical, but adaptive reasons -- molecular data were thought to convey a reliable historical signal. If a high enough degree of similarity were observed, the molecular data indicated true (evolutionary) history, or homology. In this report, however, Michael Lee of Queensland University explains that such "optimistic views of sequence data have now been challenged by recent studies that suggest that molecular data, like morphological traits, can exhibit concerted adaptive evolution" -- meaning that molecular similarities may not always give reliable historical information. As Lee reports, of one such study,

...the mitochondrial cytochrome b gene implied...an absurd phylogeny of mammals, regardless of the method of tree construction. Cats and whales fell within primates, grouping with simians (monkeys and apes) and strepsirhines (lemurs, bush-babies and lorises) to the exclusion of tarsiers. Cytochrome b is probably the most commonly sequenced gene in vertebrates, making this surprising result even more disconcerting. (p. 177)

Lee concludes that "morphological and molecular systematics might have more in common than previously assumed" (p. 178), meaning that misleading similarities, long the bane of classical evolutionary systematics, may also infect molecular data.

12. Detlef D. Leipe, L. Aravind, and Eugene V. Koonin, "Did DNA replication evolve twice independently?" Nucleic Acids Research 27 (1999): 3389-3401.

Replicating one's store of genetic information (DNA) is a basic process in all known organisms. While functional similarities exist among bacterial and eukaryotic (and archaeal) DNA replication systems, many of the component proteins of their respective replication machines are, surprisingly, non-homologous. As Detlef Leipe (of Department of Biology at Texas A & M University) and his co-workers explain,

DNA replication is an essential, central feature of cellular life....It is therefore surprising that the protein sequences of several central components of the DNA replication machinery, above all the principal replicative polymerases, show very little or no sequence similarity between bacteria and archaea/eukaryotes. (p. 3389)

Given these fundamental differences in basic cellular machinery, Leipe et al. suggest that the process of DNA replication may have evolved at least twice independently -- a hypothesis quite unexpected on neo-Darwinian (common ancestry) assumptions. "The hypothesis of an independent evolution of DNA replication," conclude Leipe et al., "offers a parsimonious explanation for the strange assortment of apparently unrelated, homologous but not orthologous and orthologous components in the DNA replication machineries of bacteria and archaea/eukaryotes" (p. 3401).

13. Peter J. Lockhart and Sydney A. Cameron, "Trees for bees," Trends in Ecology and Evolution 16 (2001): 84-88.

The relationships of the four major groups of bees (the highly eusocial honey bees, the stingless bees, the bumble bees, and the solitary orchid bees) presents a classic challenge to evolutionary analysis. Lockhart (Massey University, New Zealand) and Cameron (the University of Arkansas) explain that "molecular and morphological data have suggested strikingly different phylogenetic relationships among corbiculate bee tribes" (pp. 84-85), an unresolved problem that they conclude does not stem from the different methods used by different investigators trying to reconstruct the history of the bees. "Disagreement exists because analyses of [DNA] sequences and morphology suggest different hypotheses, and not because researchers have used different criteria for building and testing evolutionary trees" (p. 87).

14. David P. Mindell, Michael D. Sorenson, and Derek E. Dimcheff, "Multiple independent origins of mitchondrial gene order in birds," Proceedings of the National Academy of Sciences USA 95 (1998): 10693-10697.

The genetic information possessed by mitochondria, cell organelles with their own small complement of DNA (in a circular chromosome coding for 37 proteins, usually abbreviated as "mtDNA"), has been widely viewed as a good marker of phylogeny: the historical branching pattern that links organisms. In this study, however, David Mindell of the University of Michigan and his colleagues found that the specific order of mtDNA in birds "has had multiple independent originations...based on sampling of 137 species representing 13 traditionally recognized orders." This suggests that -- contrary to expectations -- patterns such as gene order may be under functional constraints. If so, mtDNA may be subject to the same kind of historically misleading similarities that affect other types of systematic data. "Our finding of multiple independent origins for a particular mtDNA gene order among diverse birds," conclude Mindell et al., "and findings by others of convergent evolution for mt sequence duplications in snakes and lizards...suggests that some constraints on gene order mutation are in effect" (p. 10696). This may considerably complicate the use of mtDNA as a historical marker in evolutionary studies.

15. Paul Morris and Emily Cobabe, "Cuvier meets Watson and Crick: the utility of molecules as classical homologies," Biological Journal of the Linnean Society 44 (1991): 307-324.

Molecular data are widely employed in attempts to reconstruct the history of life -- in large measure because such evidence is thought to be free from the interpretative difficulties that have plagued anatomical and other larger-scale data since Darwin's time. This article by the evolutionary theorist Paul Morris of Harvard University (and his colleague Emily Cobabe, at the time of publication working at the University of Bristol) challenges this viewpoint, however, suggesting that "similar or even chemically identical molecules may be unrelated" (p. 307). If molecules (like morphology) is under strong functional constraints, similarities may indicate not history, but equivalent functional demands faced by diverse organisms. "As with anatomical data," Morris and Cobabe conclude, "structural identity in molecules is not always indicative of relatedness. Molecules can be highly structurally and functionally constrained. In proteins, this may require a demonstration of homology beyond sequence identity" (p. 322).

16. Arcady R. Mushegian, James R. Garey, Jason Martin, and Leo X. Liu, "Large-Scale Taxonomic Profiling of Eukaryotic Model Organisms: A Comparison of Orthologous Proteins Encoded by the Human, Fly, Nematode, and Yeast Genomes," Genome Research 8 (1998):590-598.

The authors of this article work in the growing field of bioinformatics, where large amounts of genetic data are analyzed (by computer) for patterns of similarity and difference. In this study, Mushegian and his colleagues found that "different proteins generate different phylogenetic tree topologies" (p. 591), meaning that some proteins may give an "incorrect" evolutionary history for the organisms from which they have been taken. Protein A, for instance, may indicate that humans and flies are more closely related, whereas Protein B may indicate that humans and nematodes are more closely related. Mushegian et al. advise that genetic and protein data should be treated with caution as markers of evolutionary history, because "different proteins can generate different apparent tree topologies [evolutionary histories], strongly suggesting that historical phylogenies should not be inferred based on a single protein-coding gene" (p. 596).

17. Gavin J. P. Naylor and Wesley M. Brown, "Amphioxus Mitochondrial DNA, Chordate Phylogeny, and the Limits of Inference Based on Comparisons of Sequences," Systematic Biology 47 (1998): 61-76.

A popular perception (even among evolutionary biologists) is that molecular lines of evidence -- in particular, DNA sequence data -- strongly confirm more classical lines of evidence, such as fossils, and anatomical data drawn from extant species. In this study, however, by two molecular systematists Gavin Naylor (Zoology & Genetics, Iowa State University) and Wesley Brown (Biology, University of Michigan), mitochondrial DNA (mtDNA) drawn from 19 animal species failed "to yield the widely accepted phylogeny for chordates, and, within chordates, for vertebrates" (p. 61). This incorrect result was generated no matter what analytical method was used:

Given the breadth and the compelling nature of the data supporting [the expected] phylogeny, relatioships supported by the mitochondrial sequence comparisons are almost certainly incorrect, despite their being supported by equally weighted parsimony, distance, and maximum-likelihood analyses. The incorrect groupings probably result in part from convergent base-compositional similarities among some of the taxa, similarities that are strong enough to overwhelm the historical signal. (p. 61)

If convergence afflicts molecular data in ways "strong enough to overwhelm the historical signal," then analyzing DNA and protein similarities may not provide the royal road to the true history of life, any more than classical lines of comparative evidence could.

18. Colin Patterson, David M. Williams, and Christopher J. Humphries, "Congruence Between Molecular and Morphological Phylogenies," Annual Review of Ecology and Systematics 24 (1993): 153-188.

The authors, at the time of the publication of this paper all working at the British Museum of Natural History (Patterson is now deceased), argue that the widespread view that "molecules confirm morphology" in evolutionary studies is a myth: "...in practice, we find that incongruence between molecular trees (generated from different data sets or by different analytical methods) is as striking or pervasive as is incongruence between trees generated by morphologists" (p. 153). They conclude that "as morphologists with high hopes of molecular systematics, we end this survey with our hopes dampened. Congruence between molecular phylogenies is as elusive as it is in morphology and as it is between molecules and morphology" (p. 179).

19. Michael K. Richardson et al., "There is no highly conserved stage in the vertebrates: implications for current theories of evolution and development," Anatomy and Embryology 196 (1997): 91-106.

Biology textbooks for decades have featured drawings purporting to show that vertebrate embryos begin development looking essentially the same, and only later diverge to their characteristic morphologies. Michael Richardson, a British embryologist, and an international team of co-workers inspected actual vertebrate embryos and found that the textbooks diagrams (which trace to the 19th century German embryologist Ernst Haeckel) are false and misleading. There is no single stage of embryogenesis in vertebrates where all forms are similar: "The wide variation in morphology among vertebrate embryos is difficult to reconcile with the idea of a phylogenetically-conserved tailbud stage, and suggests that at least some developmental mechanisms are not highly constrained" (p. 91).

20. Kensal E. van Holde, "Respiratory proteins of invertebrates: Structure, function and evolution," Zoology: Analysis of Complex Systems 100 (1998): 287-297.

Oxygen carriers such as hemoglobin are vitally important proteins throughout the animals. But other oxygen-carrying molecules are utilized as well, such as hemocyanin (which uses a copper, not Fe-heme, binding site). The phylogenetic distribution of oxygen-carrying molecules is very puzzling, however, and cannot be easily fitted into current models of animal evolution. As Kensal van Holde (Biochemistry, Oregon State University) explains, "the phylogenetic distribution of the whole group of oxygen transport proteins cannot easily be reconciled with many current models of metazoan evolution." After reviewing the contradictions between the distribution of oxygen carriers and hypotheses of animal evolution, van Holde concludes that "it seems likely that we need much more information before all parts of the puzzle can be fitted together" (p. 296).

21. Kenneth Weiss, "We Hold These Truths to Be Self-Evident," Evolutionary Anthropology 10 (2001):199-203.

Kenneth Weiss is the Evan Pugh Professor of Anthropology and Genetics at Penn State University. In this article, he argues that evolutionary biology relies far more on axioms -- unprovable assumptions -- than many biologists are willing to admit. He writes:

The prevailing cosmology that greeted Darwin's Origin of Species in 1859 rested on the theologically based assumption that the universe was created at a single point in time by a purposive intelligence who selected a bestiary of species designed to be adapted to their environments. This was assumed to be given truth rather than something one had to infer from observation. By comparison, in biology we believe we are practicing a rigorous, objective, empirical method-of-knowing that does not rest on wishful thinking. Yet much of our work rests on axioms -- conventional wisdom or laws of Nature, if you will -- that we assume to be true, but cannot actually prove. (p. 199)

Weiss ends by saying "It is healthy to be skeptical even of truths we hold to be self-evident, and to ask: suppose it isn't true -- what would follow? Do we need a theory of evolutionary biology?" (Please note that in his footnotes, Weiss is highly skeptical of creationism, and endorses what he calls "the fact" of evolution.)

22. Carl Woese, "The universal ancestor," Proceedings of the National Academy of Sciences USA 95 (1998): 6854-6859.

Probably no scientist has more influenced our current understanding of the base of the Tree of Life than the microbiologist Carl Woese of the University of Illinois. The widely-accepted tripartite division of life into the Archae, the Bacteria, and the Eukarya, is due to Woese's work using ribosomal RNA (rRNA) patterns. In this provocative paper, Woese suggests that Darwin's single Tree of Life, terminating in a single common ancestor (often abbreviated LUCA, for the Last Universal Common Ancestor), may never have existed. "It is time," Woese argues, "to question underlying assumptions" (p. 6855). The problem stems from the failure of molecules to provide a consistent story for the early history of life. "No consistent organismal phylogeny has emerged from the many individual protein phylogenies so far produced," Woese writes. "Phylogenetic incongruities can be seen everywhere in the universal tree, from its root to the major branchings within and among the various taxa to the makeup of the primary groupings themselves" (p. 6854). Thus, if the LUCA existed, it was not an organism like any that we would recognize. "The universal ancestor is not an entity, not a thing. It is a process characteristic of a particular evolutionary stage" (p. 6858). The Tree of Life does not have a single root. Rather, stresses Woese, "we are left with no consistent and satisfactory picture of the universal ancestor" (p. 6855), and biology must comes to grips with this.

Questions of Process

23. Robert L. Carroll, "Towards a new evolutionary synthesis," Trends in Ecology and Evolution 15 (2000):27-32.

Robert Carroll is a professor in the Department of Biology and Curator of Vertebrate Paleontology at the Redpath Museum of McGill University (Montreal). In this article, Carroll argues that macroevolutionary changes cannot be derived from microevolutionary processes:

Increasing knowledge of the fossil record and the capacity for accurate geological dating demonstrate that large-scale patterns and rates of evolution are not compatible with those hypothesized by Darwin on the basis of extrapolation from modern populations and species....The most striking features of large-scale evolution are the extremely rapid divergence of lineages near the time of their origin, followed by long periods in which basic body plans and ways of life are retained. What is missing are the many intermediate forms hypothesized by Darwin, and the continual divergence of major lineages into the morphospace between distinct adaptive types. (p. 27)

Carroll concludes that a new evolutionary synthesis is needed, to explain such patterns as "the extreme speed of anatomical change and adaptive radiation" of the Cambrian Explosion, when "almost all of the advanced phyla [animal body plans] appeared" (p. 27).

24. Douglas Erwin, "Macroevolution is more than repeated rounds of microevolution," Evolution & Development 2 (2000):78-84.

Douglas Erwin is a paleontologist on the staff of the National Museum of Natural History (at the Smithsonian), and one of the leading critics of claims that microevolutionary processes suffice to explain macroevolutionary patterns. In this article, Erwin challenges the standard view of evolution, and argues that other processes and mechanisms are needed:

Microevolution provides no satisfactory explanation for the extraordinary burst of novelty during the late Neoproterozoic-Cambrian radiation (Valentine et al. 1999; Knoll and Carroll 1999), nor the rapid production of novel plant architectures associated with the origin of land plants during the Devonian (Kendrick and Crane 1997), followed by the origination of most major insect groups (Labandeira and Sepkoski 1993). (p. 81)

The gap between microevolution and macroevolution, Erwin contends, is real: "These discontinuities impart a hierarchical structure to evolution, a structure which impedes, obstructs, and even neutralizes the effects of microevolution" (p. 82). Much more work is needed, Erwin concludes, before we can claim to understand macroevolution.

25. Scott F. Gilbert, Grace A. Loredo, Alla Brukman, and Ann C. Burke, "Morphogenesis of the turtle shell: the development of a novel structure in tetrapod evolution," Evolution & Development 3 (2001): 47-58.

26. Olivier Rieppel, "Turtles as Hopeful Monsters," BioEssays 23 (2001): 987-991.

The origin of turtles, with their distinctive shells, has long been an evolutionary enigma. "The turtle shell," write Scott Gilbert (Embryology, Swarthmore College) and his colleagues, "represents a classic evolutionary problem: the appearance of a major structural adaptation." Could the characteristic features of turtles have arisen gradually, in a long series of Darwinian steps? "The problem for an evolutionary biologist," comments systematist and reptile expert Olivier Rieppel of the Field Museum (Chicago), "is to explain these transformations in the context of a gradualistic process" (p. 990). But the first turtle in the fossil record appears abruptly, fully turtle: "The Chelonian Bauplan [turtle body plan] appears in the fossil record," Gilbert et al. observe, "without intermediates, and the relationship of turtles to other amniote orders is not certain." What inference should one draw from these patterns of evidence? "The absence of intermediates or transitional forms in the fossil record," speculate Gilbert et al. -- especially when the fossil record is coupled with the developmental and anatomical novelties exhibited by turtles -- "could indicate that turtles arose saltationally" (p. 56). That is, turtles did not evolve by a gradual Darwinian process; as Rieppel describes this hypothesis, turtles may be "hopeful monsters." (Neither Rieppel nor Gilbert and colleagues, however, provide a detailed model of this rapid evolutionary transition, but rather refer to the need for further research.)

27. Scott F. Gilbert, John M. Opitz, and Rudolf A. Raff, "Resynthesizing Evolutionary and Developmental Biology," Developmental Biology 173 (1996): 357-372.

In this major statement about the pressing need for a new theory of evolution, biologists Gilbert (Swarthmore), Opitz (Montana State), and Raff (Indiana University) argue that while the neo-Darwinian synthesis was a "remarkable achievement," it fails to explain many of the most important phenomena of biology:

...starting in the 1970s, many biologists began questioning its adequacy in explaining evolution. Genetics might be adequate for explaining microevolution, but microevolutionary changes in gene frequency were not seen as able to turn a reptile into a mammal or to convert a fish into an amphibian. Microevolution looks at adaptations that concern the survival of the fittest, not the arrival of the fittest. As Goodwin (1995) points out, "the origin of species -- Darwin's problem -- remains unsolved." (p. 361)

Under the new synthesis that these authors propose, in which the processes of development are integrated into evolutionary understanding, "the role of natural selection...is seen to play less an important role. It is merely a filter for unsuccessful morphologies" (p. 368).

28. George L. Gabor Miklos, "Emergence of organizational complexities during metazoan evolution: perspectives from molecular biology, palaeontology and neo-Darwinism," Mem. Ass. Australas. Palaeontols. 15 (1993): 7-41.

George Miklos is an evolutionary geneticist at the Centre for Molecular Structure and Function of the Australian National University. In this article, Miklos levels a major, across-the-board indictment of neo-Darwinism. The flavor of the indictment can be gathered from the opening six sentence of the abstract:

The popular theory of evolution is the modern synthesis (neo-Darwinism), based on changes in populations underpinned by the mathematics of allelic variation and driven by natural selection. It accounts more for adaptive changes in the colouration of moths, than in explaining why there are moths at all. This theory does not predict why there were only 50 or so modal body plans, nor does it provide a basis for rapid, large scale innovations. It lacks significant connection with embryogenesis and hence there is no nexus to the evolution of form. It fails to address the question of why the anatomical gaps between phyla are no wider today than there were at their Cambrian appearance. It has no predictions about macromolecules and cellular evolution in the Archaean, about evolution via symbiogenesis, nor the manner in which cells and organisms alter and revise their genomic rules as they evolve. (p. 7)

Miklos's primary argument concerns the irrelevance -- to the solution of the problem of macroevolution -- of the scale of variation typically observed in neo-Darwinian studies, e.g., gene frequency (or allelic) shifts:

Allelic changes in natural populations are almost totally oblique to understanding the events that gave rise to the major metazoan body plans. Studies of speciation are targeting the evolutionary peripheries, and missing the significant metazoan issue -- the origin of complex forms. (p. 29)

Neo-Darwinians, Miklos contends, have been unwilling to reevaluate their theory in the light of contrary evidence:

The modern synthesis moved evolution theory into a mathematical siding from which there has been no return. Here is a theory which, as I have shown in this essay, does not touch upon any level of detail or mechanism that impinges on large scale evolutionary complexity or novelty. Whenever data have undermined its foundations, it is the data that have been considered inadequate. Thus the traditional gradualistic view is largely at variance with the fossil record, which is largely one of episodic change followed by stasis. (p. 29)

Evolutionary theory will need to break free of neo-Darwinism, Miklos concludes, to have any hope of explaining the deep puzzle that occupied Darwin, namely, how did animals (and plants) themselves come to be? Here is his final paragraph:

Finally, it is necessary to acknowledge that after over a century of the dominant paradigm, the evolution of major complexities in the history of life has had very little to do with the origin of species. The seamless moving footway of neo-Darwinism that was to have smoothly transported us from allelic variation in natural populations to understanding body plans in different phyla has led to a cul-de-sac. The origin of phyla is not via speciation "writ large". To understand what fuelled origins of phyla, the complexities that emerged long ago from macromolecular and supracellular complexes and from symbiogenic events will need to be understood via molecular embryology, where the quintessence of evolutionary truth is to be found. (p. 34)

29. Neil H. Shubin and Charles R. Marshall, "Fossils, genes, and the origin of novelty," in Deep Time (2000, The Paleontological Society), pp. 324-340.

Shubin (Paleontology, University of Chicago) and Marshall (Paleontology and Molecular Biology, UCLA) argue that the neo-Darwinian synthesis needs to come to grips with new evidence that the theory never anticipated and has difficulty explaining:

In the last 25 years, new data from genetics have dealt some profound surprises to the evolutionary biology community. Perhaps the most striking discovery is the extent to which major patterning genes and regulatory interactions are deeply conserved across vast expanses of time and phylogeny....Indeed, in many cases, the developmental role of these homologous genes is also conserved in creatures with different body plans. Strikingly, many homologous genes appear to perform the same function in structures that share functional similarities but lack a common evolutionary origin. (p. 325)

Another puzzling problem is the Cambrian Explosion: "The disconnect between rates of genetic and morphological change," write Shubin and Marshall (p. 335), "is as vexing a problem for population geneticists as it is for paleontologists." They conclude that evolutionists must bridge "the gap between microevolution and macroevolution," by seeking "the mechanisms behind the production of morphological variation" (p. 338).

30. Keith Stewart Thomson, "Macroevolution: The Morphological Problem," American Zoologist 32 (1992): 106-112.

Thomson (Oxford University) has long been disenchanted with the explanatory adequacy of neo-Darwinism. Macroevolution has resisted explanation, he argues:

While the origins of major morphological novelties remains unsolved, one can also view the stubborn persistence of macroevolutionary questioning, and particularly its revival in recent years, as a challenge to orthodoxy: resistance to the view that the synthetic theory tells us everything we need to know about evolutionary processes. (p. 106)

Although most evolutionary biologists, beginning with Darwin, saw evolutionary change as necessarily gradual, Thomson points out that "no one has satisfactorily demonstrated a mechanism at the population genetic level by which innumerable very small phenotypic changes could accumulate rapidly to produce large changes: a process for the origin of the magnificently improbable from the ineffably trivial" (p. 107, emphasis in original).

31. Bärbel M.R. Stadler, Peter F. Stadler, Günther P. Wagner, and Walter Fontana, "The Topology of the Possible: Formal Spaces Underlying Patterns of Evolutionary Change," Journal of Theoretical Biology 213 (2001):241-274.

32. Günther P. Wagner, "What is the Promise of Developmental Evolution? Part II: A Causal Explanation of Evolutionary Innovations May Be Impossible," Journal of Experimental Zoology (Mol Dev Evol) 291 (2001): 305-309.

In these companion papers, theoretical biologist Günther Wagner (Yale University) and his colleagues argue that neo-Darwinism fails to explain many important biological phenomena, and that the relationship of these phenomena "to the mechanistic theory of evolutionary change, as represented by population genetics, remains unclear and tense" (JTB, p. 242). They suggest that this failure of explanation stems from the underlying assumptions of neo-Darwinism, such as that any evolutionary change is readily accessible to natural selection. Patterns of evidence, however, indicate that "this fluidity is largely a fiction and point at profound asymmetries in the accessibility of phenotypic and genetic states" (JTB, p. 242), meaning that many evolutionary transitions may be all but impossible. Going even further, Wagner contends that many important historical events in evolution may be forever inexplicable, because the conditions needed to understand those events -- in particular, the genetic background to the changes in question -- may be lost irretrievably. If this is the case, he writes, "then it might be impossible to experimentally demonstrate exactly which genetic changes caused the evolutionary innovation" (JEZ, p. 308, emphasis in original).

Questions about the Central Issue: the Origin and Nature of Biological Complexity

33. Philip Ball, "Life's lessons in design," Nature 409 (2001): 413-416.

What might we learn from biological objects that could be applied to improving our own technologies? The research field of biomimetics tries to answer this question by looking closely at natural systems, and "reverse-engineering" them for solutions to similar technological problems faced by humanly-constructed artifacts. Questions of scale and complexity, of course, arise immediately, as Philip Ball (an editor at the journal Nature) notes:

One of the biggest obstacles to taking full advantage of what nature has to offer is that the living world has an awesomely elaborate means of construction. There is no assembly plant so delicate, versatile and adaptive as the cell. (p. 413)

The astonishing subtlety of biological designs beggars description; or, to put it another way, one cannot assume that every solution to a functional challenge will be intuitively obvious on first inspection. Consider, for instance, insect flight:

Specifically, insects are conjurors of the vortex. With deft flappings and rotations of their wings, they are able to manipulate the vortices shed from the edges to control their motion in ways that flight engineers can only dream of: taking off backwards, for example, or landing upside down. By such means, insects subvert the "conventional" aerofoil principles of flight, giving rise to the canard that the bee is aerodynamically impossible. In essence, the flight of the bumble-bee is a flight beyond the dynamic steady state: lift is generated at particular, exquisitely timed moments during the flap cycle. By rotating the wing so that it is parallel to the ground on the downstroke but perpendicular on the recovery stroke, an insect is able to recapture energy from the vortices shed from the wing edge. This reveals a new mechanism for flight that one could hardly have deduced from first principles, and which might be adopted for the development of miniaturized robotic flyers for remote sensing, surveying and planetary exploration. (p. 414)

Eventually, Ball argues, engineers seeking to learn from biology must turn to the realities of the microscopic realm. Synthetic silk, for instance, has yet to become a commercially successful product, not because we do not understand the biochemistry or genetics of silk production, but because real silk gains its strength from more than its protein structure:

It is the weaving of strands in the spinneret that gives them their strength. The details of this process are not understood; but it may be that not until we can build an artificial, miniaturized spinning mechanism will silk be an industrial material.

This is why biomimetics must reach down to the microscopic and ultimately the molecular scale. Some of nature's best tricks are conceptually simple and easy to rationalize in physical or engineering terms; but realizing them requires machinery of exquisite delicacy. (p. 416)

Ball concludes that the horizon of knowledge opened by biomimetics is vast and continues to grow:

...fundamental research on the character of nature's mechanisms, from the elephant to the protein, is sure to enrich the pool from which designers and engineers can draw ideas. The scope for deepening this pool is still tremendous. It is at the molecular scale, however, that we will surely see the greatest expansion of horizons, as structural studies and single-molecule experiments reveal the mechanics of biomolecules. If any reminder were still needed that nanotechnology should not seek to shrink mechanical engineering, cogs and all, to the molecular scale, it is found here. Nature's wheel -- the rotary motor of the bacterial flagellum -- never got any larger than this, nor is it fashioned from hard, wear-resistant materials, nor is driven electromagnetically or by displacement of a piston. But it is efficient, fast, linear and reversible. Somewhere there is a lesson in that. (p. 416)

34. Rodney Brooks, "The relationship between matter and life," Nature 409 (2001): 409-411.

Rodney Brooks of the Artificial Intelligence Laboratory at MIT has long been a pathbreaking investigator in the construction of "AI" (artificial intelligence) and "Alife" (artificial life) systems. In this skeptical article, however, Brooks steps back from the bench to look critically at what AI and Alife research has actually demonstrated. He writes:

...both fields have been labelled as failures for not having lived up to grandiose promises. At the heart of this disappointment lies the fact that neither AI nor Alife has produced artefacts that could be confused with a living organism for more than an instant. AI just does not seem as present or aware as even a simple animal and Alife cannot match the complexities of the simplest forms of life. (p. 409)

The failures of these fields, Brooks argues, requires a diagnosis:

We build models to understand the biological systems better, but the models never work as well as biology. We have become very good at modelling fluids, materials, planetary dynamics, nuclear explosions and all manner of physical systems. Put some parameters into a program, let it crank, and out come accurate predictions of the physical character of the modelled system. But we are not good at modelling living systems, at small or large scales. Something is wrong. (p. 410)

After considering several modest "fixes" for AI and Alife (e.g., incorrect parameters, lack of computing power, lack of complexity in models), Brooks turns to a more challenging diagnosis: "we might be missing something fundamental and currently unimagined in our models of biology" (p. 410). He argues:

We would then need to find new ways of thinking about living systems to make any progress, and this will be much more disruptive to all biology. ... So what might be the nature of this unimagined feature of life? One possibility is that some aspect of living systems is invisible to us right now. The current scientific view of living things is that they are machines whose components are biomolecules. It is not completely impossible that we might discover some new properties of biomolecules or some new ingredient. One might imagine something on a par with the discovery of X-rays a century ago, which eventually led to our still-evolving understanding of quantum mechanics. Relativity was the other such discovery of the twentieth century, and had a similarly disruptive impact on the basic understanding of physics. Some similar discovery might rock our understanding of the basis of living systems. (p. 410)

35. David W. Deamer, "The First Living Systems: a Bioenergetic Perspective," Microbiology and Molecular Biology Reviews 61 (1997): 239-261.

Could living systems have arisen without a means of transferring energy from the environment to the primitive cell, in order to do the work characteristic of all organisms? Biochemist and origin-of-life researcher David W. Deamer, of the University of California-Santa Cruz, argues that current models for the evolution of life itself neglect this critical question. To bring the point home with clarity and force, Deamer suggests a thought experiment in which a prebiotic "soup" of non-living chemicals is gradually made more complex, "using what we know about the composition of a living cell" (p. 241). In no case, he argues, would a living system arise, without a means for capturing and transferring energy. He writes:

Imagine that on the early Earth, a complete system of catalytic and information-bearing molecules happened by chance to come together in a tide pool that was sufficiently concentrated to produce the equivalent of the contents of our flask. We could model this event in the laboratory by gently disrupting a live bacterial culture, subjecting it to a sterilizing filtration step, and adding the mixture to the flask of nutrient broth. No living cells are present, but entire bacterial genomes are available, together with ribosomes, membranous vesicles, ATP and other energy-containing substrates, and thousands of functional enzymes. Once again, would a living system arise under these conditions? Although Kauffman might be optimistic about the possibilities, most experimentalists would guess that little would happen other than slow, degradative reactions of hydrolysis, even though virtually the entire complement of molecules associated with the living state is present. The dispersion has lost the extreme level of order characteristic of cytoplasm in contemporary living cells. Equally important is that the ATP would be hydrolyzed in seconds, so that the system still lacks a continuous source of free energy to drive the metabolism and polymerization reactions associated with life. (p. 242)

Deamer suggests future directions of research to bring greater realism to origin-of-life theories, stressing that encapsulation (isolation from the environment) is a necessary condition for any plausible protobiont.

36. Michael J. Katz, Templets and the explanation of complex patterns, Cambridge: Cambridge University Press, 1986.

The first usage of the term "irreducibly complex" in the scientific literature was not due to Michael Behe of Lehigh University (although Behe certainly put his stamp on the term, and has given it wide currency). Ten years before Darwin's Black Box was published, the theoretical biologist Michael J. Katz of Case Western Reserve University (Cleveland, Ohio) published an eight chapter scientific monograph with Cambridge University Press, entitled Templets and the Explanation of Complex Patterns (1986). In that publication, "irreducible complexity" occurs as an index entry, and is explained in the text as follows:

In the natural world, there are many pattern-assembly systems for which there is no simple explanation. There are useful scientific explanations for these complex systems, but the final patterns that they produce are so heterogeneous that they cannot effectively be reduced to smaller or less intricate predecessor components. As I will argue in Chapters 7 and 8, these patterns are, in a fundamental sense, irreducibly complex...(pp. 26-27)

In context, it is abundantly clear that by "irreducible complexity," Katz refers essentially to the same phenomena as does Behe. "For some natural phenomena," he writes, "there simply is no reduction to smaller predecessors. In these cases, the companion rule to 'order stems from order' is that 'complexity stems from complexity'" (p. 90). More fully:

...the unique characteristics of organisms are pattern characteristics. The first of these fundamental pattern characteristics is complexity. Cells and organisms are quite complex by all pattern criteria. They are built of heterogeneous elements arranged in heterogeneous configurations, and they do not self-assemble. One cannot stir together the parts of a cell or of an organism and spontaneously assemble a neuron or a walrus: to create a cell or an organisms one needs a preexisting cell or a preexisting organism, with its attendant complex templets. A fundamental characteristic of the biological realm is that organisms are complex patterns, and, for its creation, life requires extensive, and essentially maximal, templets. (p. 83)

Like Behe, Katz confronts the issue of the origin of life, and the dilemma raised for reductive or naturalistic explanation by the complexity of even the simplest organisms:

Today's organisms are fabricated from preexisting templets -- the templets of the genome and the remainder of the ovum [egg] -- and these templets are, in turn, derived from other, parent organisms. The astronomical time scale of evolution, however, adds a dilemma to this chain-of-templets explanation: the evolutionary biologist presumes that once upon a time organisms appeared when there were no preexisting organisms. But, if all organisms must be templeted, then what were the primordial inanimate templets, and whence came those templets? (pp. 65-66)

The parallels between Katz's argument, and those of design theorists such as Michael Behe, William Dembski, or Stephen Meyer, are so numerous and striking that if one did not know better, one might assume that a design theorist had written this (and dozens of other such passages in Katz's book):

Self-assembly does not fully explain the organisms that we know; contemporary organisms are quite complex, they have a special and an intricate organization that would not occur spontaneously by chance. The "universal laws" governing the assembly of biological materials are insufficient to explain our companion organisms: one cannot stir together the appropriate raw materials and self-assemble a mouse. Complex organisms need further situational constraints and, specifically, they must come from preexisting organisms. This means that organisms -- at least contemporary organisms -- must be largely templeted. (p. 65)

37. Claire M. Fraser et al., "The Minimal Gene Complement of Mycoplasma genitalium," Science 270 (1995): 397-403.

38. Clyde A. Hutchison et al., "Global Transposon Mutagenesis and a Minimal Mycoplasma Genome," Science 286 (1999): 2165-2169.

39. Eugene V. Koonin, "How Many Genes Can Make a Cell: The Minimal-Gene-Set Concept," Annual Review of Genomics and Human Genetics 1 (2000):99-116.

40. Jack Maniloff, "The minimal cell genome: 'On being the right size,'" Proceedings of the National Academy of Sciences USA 93 (1996): 1004-1006.

41. Arcady R. Mushegian and Eugene V. Koonin, "A minimal gene set for cellular life derived by comparison of complete bacterial genomes," Proceedings of the National Academy of Sciences USA 93 (1996): 10268-10273.

42. Scott N. Peterson and Claire M. Fraser, "The complexity of simplicity," Genome Biology 2 (2001):1-7.

These related articles explore the concept of a "minimal genome," and asks the question "What is the minimal number of genes necessary to support cellular life?" (p. 1). Peterson and Fraser, who work at The Institute for Genomic Research (TIGR), which led one of two international efforts to map the human genome, explain that research on the simplest known living thing, the parasitic bacterium Mycoplasma genitalium, has revealed unexpected complexity at the foundation of life:

The fact that an estimated one third of the essential set of genes in this minimal genome are of undefined function is an important result that has at least two potential interpretations. First, it draws dramatically into question a basic assumption held by many biologists that the fundamental mechanisms and functions underlying cellular life have for the most part been identified and well characterized. If approximately 100 genes in the simplest functioning cell are of unknown function and are essential to basic cellular processes, this assumption becomes quite dubious....we have much work to do before we can claim to have a clear understanding of even the simplest cell and its functions. (p. 6).

Peterson and Fraser end by pointing to what they call an "extremely interesting" possibility, namely, "that many gene functions have evolved independently more than once since the beginning of cellular life on the planet" (p. 7). Eugene Koonin, a leader in this field of research who works at the National Center for Biotechnology Information, explores the surprising discovery that only approximately 80 of the estimated 250 necessary genes are found "in all life forms" (p. 99), suggesting a much greater degree of genetic diversity among organisms, in their basic functions, than had been suspected.

43. Leslie E. Orgel, "Self-organizing biochemical cycles," Proceedings of the National Academy of Sciences 97 (2000): 12503-12507.

How did basic metabolic pathways, such as the citric acid cycle, arise from non-biological precursors? Leslie Orgel of the Salk Institute for Biological Studies, one of the world's leading origin-of-life researchers, notes that all scenarios for the spontaneous origin of metabolic cycles "have one feature in common: a self-organized cycle or network of chemical reactions that does not depend directly or indirectly on a genetic polymer" (p. 12503). In other words, starting with information-bearing molecules such as DNA or RNA is already too complex: the first metabolic system, then, must have originated in a much simpler state. Orgel is skeptical of such proposals, however:

Unfortunately, catalytic reactions of the required type in aqueous solution are virtually unknown; there is no reason to believe, for example, that any intermediate of the citric acid cycle would specifically catalyze any reaction of the citric acid cycle. The explanation of this is simple: noncovalent interactions between small molecules in aqueous solution are generally too weak to permit large and regiospecific catalytic accelerations [of the type required by living systems]. To postulate one fortuitously catalyzed reaction, perhaps catalyzed by a metal ion, might be reasonable, but to postulate a suite of them is to appeal to magic. (pp. 12504-12505)

Existing self-organization scenarios, therefore, appeal to a "near-miracle" (p. 12506), in which "one must postulate a series of remarkable coincidences to conclude that all of the reactions are catalyzed on the same mineral and that each intermediate product is formed in the correct position and orientation" (p. 12506). Orgel concludes:

The novel, potentially replicating polymers that have described up to now, like the nucleic acids, are formed by joining together relatively complex monomeric units. It is hard to see how any could have accumulated on the early earth. A plausible scenario for the origin of life must, therefore, await the discovery of a genetic polymer simpler than RNA and an efficient, potentially prebiotic, synthetic route to the component monomers. The suggestion that relatively pure, complex organic molecules might be made available in large amounts via a self-organizing, autocatalytic cycle might, in principle, help to explain the origin of the component monomers. I have emphasized the implausibility of the suggestion that complicated cycles could self-organize, and the importance of learning more about the potential of surfaces to help organize simpler cycles. (p. 12507)

44. Eörs Szarthmáry, "The evolution of replicators," Philosophical Transactions of the Royal Society of London B 335 (2000): 1669-1676.

Any Darwinian scenario for the origin of biological complexity requires replicators: systems capable of storing and transmitting information with fidelity, yet also with some capacity for variation, to allow for adaptive change. In this theoretical analysis, Eörs Szarthmáry (of the Institute for Advanced Study of the Collegium Budapest) argues that the problem of the origin of replicators is unsolved, mainly because of what he calls "the paradox of specificity" (p. 1669). In order for a self-organizing system (such as Stuart Kauffman's hypothetical autocatalytic protein nets) to exhibit more than very limited, and non-biological, heredity, it must contain a large number of different component types (i.e., molecules). But a large number of such types entails that harmful side reactions will follow: "This is due to the fact that in a simple medium there can always be side reactions, stoichiometric and catalytic, which compromise the functioning of the network as a whole -- which might otherwise look good on paper" (p. 1672). As Szarthmáry notes,

A rather large number (n) of different polypeptide sequences seems to be required for the imagined functioning of these autocatalytic protein nets (Kauffman 1986). A higher-level analogy of the side-reaction plague readily arises. Calculations of probabilities about such systems always assume that a protein may or may not catalyse a given legitimate reaction in the system but that it would not catalyse harmful side reactions. This is obviously an error. Hence the paradox of specificity strikes again -- the feasibility of autocatalytic attractor sets seems to require a large number of component types (high n), whereas the plague of side reactions calls for small systems (low n). No satisfactory solution of this problem has yet been given. (p. 1673)

Szarthmáry summarizes numerous other difficulties for the origin of replicators, such as (a) the need for a highly specific set of building blocks, and (b) chemical difficulties confronting any system of template replication, in the absence of specific enzymes. Consider (a):

There is an important precondition for successful replication of all molecular replicators--the environment must contain the right raw materials. This sounds trivial, but in fact it is not. Consider the case of RNA replication. This needs activated ribonucleotides of the right conformation. One can imagine (and in fact synthesize) mirror images of the currently used nucleotides. An RNA molecule would not be able to replicate in a medium consisting of a mixture of the left and right mirror-image nucleotides. This obstacle to prebiotic replication is called "enantiomeric cross-inhibition" (Joyce et al. 1987). Replication needs the right raw materials in the environment of the replicator. For contemporary nucleic acids this environment is highly evolved -- it is the cytoplasm of the cell, maintained to a large extent by the phenotypic effects of the genes themselves on the "vehicles" (Dawkins 1976) or "interactors" (Hull 1980) in which they are embedded and replicated. (p. 1673)

Or consider (b):

A common criterion for the replication process is that the two strands (template and copy) must spontaneously separate. Since they are held together by hydrogen bonds (also necessary for replication) the strands cannot be too long or otherwise they would stick together for too long a time. Long pieces of nucleic acids can be replicated in the cell because enzymes of the replicase complex also ensure the unwinding of the strands -- this cannot be assumed in non-enzymatic [prebiotic] systems. (p. 1672)

Szarthmáry's review provides an excellent survey of the mechanistic difficulties facing the modelling of prebiotic systems during their transition to true biological states.