History of the hereditary molecule (to 1953)

In principle:
"Genetics" was taught for 50 years
   without knowledge of the hereditary substance or its structure
     (see Orientation to Bio2250)

The story of the search for the hereditary substance includes
     superb examples of the experimental method in biology.


Two candidates: protein versus nucleic acid

Cells contain H20, lipids, carbohydrates, and ...

Mulder (1838) - Discovery of protein
        Abundant, water-soluble, nitrogenous
                "... complex... regulates cell metabolism...
                 most important component of living matter...
                 without it, life would not be possible"
        Hydrolysis of protein amino acids (~20 kinds)

Miescher (1868) - Discovery of nuclein
        Found in cell nucleus, acidic, rich in PO4,
        Lacks S (characteristic of protein)
        Now know this as nucleic acid

Levene (1910) - Tetranucleotide hypothesis
        nucleic acid is a repetitive polymer of four bases
             A:C:G:T in the approximate ratio 1:1:1:1
        Structure seems too simple to carry information

Griffith (1928) - transforming principle
        Killed virulent viruses 'transform' live avirulent viruses:
              avirulent viruses become virulent, and
              Transformation is inherited
        Hereditary makeup of organisms can be altered

Avery, MacLeod, & McCarty (1944) -
        Chemical isolation of  'transforming principle' from cells
                Transformation survives protease treatment,
                 destroyed by nuclease treatment (Homework):
        It's chemically pure deoxyribonucleic acid (DNA)  ?!?!

Hershey & Chase (1952) - 'blender experiment'
       Bacteriophages are grown in radioactive medium
             Proteins labeled with 35S
             DNA labeled with 32P
       During infection of E. coli by bacteriophages,
              32P goes in,  35S stays out
        DNA is the transforming principle

Watson & Crick (1953) "The Double Helix"

       Schrodinger (1945) "What is Life?":
              Are there "other laws of physics?"

       Franklin & Wilkins' X-ray crystallography
              DNA is a helix: two or three strands? [Photo 51]

       Chargaff's Rules : Bases are not equimolar, but occur in ratios
              [A] = [T]  &  [C] = [G]   (Table)

       Model building:
              Two or three strands, bases inside or outside
              Key recognition : A+T pair looks like C+G pair

       The Watson-Crick structure for DNA
           double-stranded helix  (3-D image)
                Two sugar-phosphate backbones outside
                Nitrogenous bases inside
                H-bonds hold strands held together

Homework:

1) What is Avery's "Assay for Transformation"? How does it relate to the presence of R and S cells in the cultures on the third line above? How does Avery's "assay" differ from Griffith's?

2) Predict the results of the Hershey-Chase experiment if they had used radioactive 14C instead of 32P

3) Is the Watson - Crick structure dependent on a knowledge gained from the Hershey-Chase experiment? Explain.


For further reading:

J Cairns, G Stent, & J Watson (1966). Phage and the Origins of Molecular Biology. Freeman.
        [Biographical essays on the early days by the founders of molecular genetics.]

E Chargaff (1978). Heraclitean Fire. Paul & Co. [Reflections of an also-ran on classical biochemistry versus modern molecular biology].

FHC Crick (1988). What Mad Pursuit? Basic Books.
        [Crick's version of the 'double helix' history, and lots more.]

L Gonick & M Wheelis (1991). The Cartoon Guide to Genetics, 2nd ed. Harper Collins.
        [A well-illustrated, entertaining primer of basic Mendelian and (dated) molecular genetics for non-biologists.]

HF Judson (1979). The Eighth Day of Creation (2nd ed.). Simon & Schuster.
        [A in-depth history of the "classical" period of molecular biology. Valuable for its interviews with the principals.]

A Sayre (1975). Rosalind Franklin and DNA. Norton.
        [An early re-appraisal of the role of Franklin, with commentary on the role of women in science.]

JD Watson (1968). The Double Helix. Athenaeum.
        [An entertaining, irreverent, and sexist account of the discovery of the structure of DNA.
         See the accounts of Crick, Wilkins, and Sayre for other views
        Re-issued in 2003 in a heavily annotated and supplemented edition by Cold Spring Harbor Labs. Includes reactions to publication]

JD Watson (2003). DNA: The Secret of Life. Knopf.
         [A narrative history of genetics and molecular biology in the 20th century,
           written for the 50th anniversary of the discovery of the DNA structure].

MHF Wilkins (2003). The Third Man of the Double Helix. Oxford.
        [See especially Chapter 8 on the exchange of crystallographic data in Photo 51]. 

All text material © 2015 by Steven M. Carr