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Evolution: The Molecular Landscape

Cold Spring Harbor’s 74th Symposium
The Molecular Landscape
Edited by Bruce Stillman,
David Stewart, and
Jan Witkowski,
Cold Spring Harbor Laboratory


Chapter 2 Notes

The Origin of Molecular Biology

The opening figure shows the four subunits of the hemoglobin molecule (p. 55 and below).

The Beginnings of Molecular Biology

The Physical Basis of Life Was Not Understood until the 1950s

Hunter (2000) describes the origins of organic chemistry.

Hunter (2000, Chapter 7) describes the evidence that led to rejection of the colloid theory.

The closing quote (p. 40) by Monod, that “the substance of the gene was something in the minds of people ... as inaccessible as the material of the galaxies” is from Judson (1995, Chapter 7).

Molecular Biology Has Roots in Several Disciplines and Techniques

The multiple roots of molecular biology are discussed by Morange (1998).

The Structure of DNA Established the Physical Basis of Heredity

The classic account of the determination of the structure of DNA is Watson’s (1968) The Double Helix; see also Crick’s (1988) autobiography, What Mad Pursuit. Judson (1995, Part 1) gives an extremely detailed account as well.

Many of Crick’s papers, together with background information, can be found here.

The DNA Sequence Is Expressed through the Genetic Code

Meselson and Stahl (1958) demonstrated the semiconservative replication of DNA (Fig. 2.20). Holmes (2001) gives a detailed history of what has been called “the most beautiful experiment in biology.” See also Judson (1995, Chapter 3).

Ingram’s determination of the single-amino-acid difference between normal and sickle-cell hemoglobin (Fig. 2.21) was published in 1956.

Judson (1995, Chapter 5) gives a detailed account of how the genetic code was deciphered. Gamow (1954) proposed that amino acids bind directly to pockets in the double helix. Crick et al. (1957) published a proposal for a “comma-less code,” which makes sense only in one reading frame. Crick et al. (1961) correctly summarize the key features of the genetic code. Ultimately, the code could not be deciphered by logical arguments of this kind, because the code is essentially arbitrary. It was eventually solved by translating synthetic RNA fragments in vitro.

The Genetic Code Was Deciphered Primarily by Painstaking Biochemistry

Work on the biochemistry of nucleic acids was brought together at a symposium in Cambridge in 1946 (Judson 1995, pp. 237–238), with papers published in the following year. Brachet (1947) first suggested that ribosomes are the site of protein synthesis.

Nirenberg and Matthaei (1961) published the first results from their in vitro system for protein synthesis, showing that UUU codes for phenylalanine.

Crick (1966) summarized the genetic code, just after all 64 triplet codons had been assigned.

The First Gene Regulation Mechanism Was Discovered by Jacob and Monod

Ptashne (2004) summarizes the mass of work to date on bacteriophage λ.

Judson (1995, Chapter 7) details the work on the lac system and bacteriophage λ that led Jacob and Monod (1961) to their understanding of gene regulation. The crucial PaJaMo experiment was published as Pardee et al. (1959).

The Central Dogma: DNA Makes RNA Makes Protein

The slogan “DNA makes RNA makes protein” was coined surprisingly early by Boivin and Vendrely (1947); see Judson (1995, p. 237). Crick (1958) first set out the “Central Dogma.” For a discussion in the light of the discovery of reverse transcriptase, see Crick (1970).

Judson (1995, Chapter 7) describes the crucial meeting between the Paris and Cambridge groups on Good Friday, 1960.

Jacob and Monod (1961) explain the basic mechanisms of protein synthesis and gene regulation.

Protein Function Depends on Changes in Shape: Allostery

Judson (1995, Part III) describes how protein structure was understood.

Monod, Changeux, and Jacob (1963) explained the importance of allostery in 1962; it was published the following year (see also Monod 1971).

Ferry (2007) wrote a recent biography of Perutz (see also Perutz 1962, Fig. 12, p. 665).

Direct Observation of DNA Revealed Some (but Surprisingly Few) New Phenomena

Morange (1998) describes developments in molecular biology since the 1970s.

The discovery and significance of catalytic RNA are described in Cech (1989) and Altman’s (1989) Nobel Lectures, given in 1989.

For the importance of catalytic RNA in the origin of life, see Chapter 4.

Evolutionary and Molecular Biology: A New Synthesis?

Molecular Biology Opened Up Study of How All Life Evolves

For more on classical genetic markers and the discovery of extensive molecular variation, see pp. 358–363.

The example of the molecular clock in Figure 2.38 is from Figure 4.4 of Kimura (1983).

The Pattern of Molecular Variation Suggested That Most of It Does Not Affect Fitness: The “Neutral Theory”

The neutral theory was proposed independently by Kimura (1968) and by King and Jukes (1969), but it was developed primarily by Kimura. See Kimura (1983), Crow (2000), and Jukes (2000).

Dietrich (1994) gives a history of the neutral theory and its reception. An interesting source for the history of molecular evolution, which includes interviews and video presentations, can be found here.

Evolutionary Questions Are Difficult to Answer

Voltaire’s optimistic Dr. Pangloss is a character in Candide.

Gould and Lewontin (1979) criticized “just so stories” in an influential article. See Web Notes for Chapter 20.

For more on exon shuffling, see Figure 8.23 and p. 712. In Chapter 23, we show how recombination can evolve because it facilitates adaptation. However, it is difficult to show that traits (such as recombination or exon shuffling) did, in fact, evolve because they aid adaptation.

Niehrs and Pollet (1999) proposed that groups of eukaryotic genes that are expressed at the same time may have evolved to be clustered together because such clustering aids evolution of new regulatory patterns. However, a more straightforward explanation is that such clusters are jointly regulated, as in bacteria.


Altman S. 1989. Enzymatic cleavage of RNA by RNA. Nobel lecture, December 8. In Nobel lectures in chemistry, 1981–1990 (ed. Malmström B.G. et al.), pp. 626–647. World Scientific Publishing Co., Singapore, 1993.

Boivin A. and Vendrely R. 1947. Sur le role possible des deux acides nucléiques dans la cellule vivante. Experientia 3: 32–34.

Brachet J. 1947. Nucleic acids in the cell and embryo. Symp. Soc. Exp. Biol. 1: 207–224.

Cech T.R. 1989. Self-splicing and enzymatic activity of an intervening sequence RNA from Tetrahymena. Nobel lecture December 8. In Nobel lectures in chemistry, 1981–1990 (ed. Malmström B.G. et al.), pp. 651–676. World Scientific Publishing Co., Singapore, 1993.

Crick F.H.C. 1958. On protein synthesis. Symp. Soc. Exp. Biol. 12: 138–163.

Crick F.H.C. 1966. The genetic code: Yesterday, today, and tomorrow. Cold Spring Harbor Symp. Quant. Biol. 31: 3–9.

Crick F.H.C. 1970. Central dogma of molecular biology. Nature 227: 561–563.

Crick F.H.C. 1988. What mad pursuit. Basic Books, New York.

Crick F.H.C., Griffith J.S., and Orgel L.E. 1957. Codes without commas. Proc. Natl. Acad. Sci. 43: 416–421.

Crick F.H.C., Barnett L., Brenner S., and Watts-Tobin L.J. 1961. General nature of the genetic code for proteins. Nature 192: 1227–1232.

Crow J.F. 2000. Thomas H. Jukes. Genetics 154: 955–956.

Dietrich M.R. 1994. The origins of the neutral theory of molecular evolution. J. Hist. Biol. 27: 21–59.

Ferry G. 2007. Max Perutz and the secret of life. Chatto and Windus, London.

Gamow G. 1954. Possible relations between deoxyribonucleic acid and protein structures. Nature 173: 318.

Gould S.J. and Lewontin R. 1979. The spandrels of San Marco and the Panglossian paradigm. Proc. R. Soc. Lond. B 205: 581–595.

Holmes F.L. 2001. Meselson, Stahl, and the replication of DNA: A history of “the most beautiful experiment in biology.” Yale University Press, New Haven, Connecticut.

Hunter G.K. 2000. Vital forces: The discovery of the molecular basis of life. Academic Press, New York.

Ingram V. 1956. A specific chemical difference between the globins of normal human and sickle-cell anaemia haemoglobin. Nature 178: 792–794.

Jacob F. and Monod J. 1961. Genetic regulatory mechanisms in the synthesis of proteins. J. Mol. Biol. 3: 318–356.

Judson H.F. 1995. The eighth day of creation. Penguin, London.

Jukes T.H. 2000. The neutral theory of molecular evolution. Genetics 154: 956–958.

Kimura M. 1968. Evolutionary rate at the molecular level. Nature 217: 624–626.

Kimura M. 1983. The neutral theory of molecular evolution. Cambridge University Press, Cambridge.

King J.L. and Jukes T.H. 1969. Non-Darwinian evolution. Science 164: 788–798.

Monod J. 1971. Chance and necessity: An essay on the natural philosophy of modern biology. Alfred A. Knopf, New York.

Monod J., Changeux J.-P., and Jacob F. 1963. Allosteric proteins and cellular control systems. J. Mol. Biol. 3: 306–329.

Meselson M. and Stahl F.W. 1958. The replication of DNA in Escherichia coli. Proc. Natl. Acad. Sci. 44: 671–682.

Morange M. 1998. A history of molecular biology. Harvard University Press, Cambridge, Massachusetts.

Niehrs C. and Pollet N. 1999. Synexpression groups in eukaryotes. Nature 402: 483–488.

Nirenberg M.W. and Matthaei J.H. 1961. The dependence of cell-free protein synthesis in E. coli upon naturally occurring or synthetic polyribonucleotides. Proc. Natl. Acad. Sci. 47: 1588–1602.

Pardee A.B., Jacob F., and Monod J. 1959. The genetic control and cytoplasmic expression of inducibility in the synthesis of β-galactosidase in E. coli. J. Mol. Biol. 1: 165–178.

Perutz M.E. 1962. X-ray analysis of haemoglobin. Nobel lecture December 11. In Nobel Lectures, Chemistry 1942–1962, pp. 653–673. Elsevier, Amsterdam, 1964.

Ptashne M. 2004. A genetic switch: Phage lambda revisited, 3rd ed. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York.

Watson J.D. 1968. The double helix. Penguin, London.


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