Laying the Foundation of Molecular Biology:

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2 Laying the Foundation of Molecular Biology: Max Delbrück and Salvador Luria; Ed Tatum and Joshua Lederberg; Marsha Chase and Al Hershey; Jim Watson and Francis Crick The great speed at which the basic facts of molecular genetics emerged following the discovery of the double helix was possible only because of a prior decision taken collectively in the mid-1940s by a small group of younger scientists interested in the nature of the genes. Jim Watson (1983)

3 James D. Watson Drosophila s better days were over and... many of the best younger geneticists... worked with microorganisms. On beginning graduate school at the University of Indiana in 1947

4 Drosophila melanogaster

5 What is the nature of the elements of heredity that Mendel postulated as purely theoretical units? What are genes? Now that we locate them in the chromosomes are we justified in regarding them as material units; as chemical bodies of a higher order than molecules? Frankly, these are questions with which the working geneticist has not much concern himself, except now and then to speculate as to the nature of the postulated elements. There is no consensus of opinion amongst geneticists as to what the genes are whether they are real or purely fictitious because at the level at which the genetic experiments lie, it does not make the slightest difference whether the gene is a hypothetical unit, or whether the gene is a material particle. Thomas Hunt Morgan s 1934 Nobel Prize Lecture

6 A new science has been born. It has caused a veritable revolution in our knowledge of virulent and contagious diseases. Louis Pasteur, 1888 The last photograph of Louis Pasteur, 1895

7 A sterilizing filter used in research. Viruses, unlike bacterium, will pass through the filter. Being filterable was a defining characteristic of viruses until 1935 From Félix d Herelle The Bacteriophage and Its Behavior (1926), p. 23

8 Tobacco Mosaic Virus (TMV) Mosaic-infected tobacco leaves, from 1898

9 The Isolation of a Crystalline Protein Possessing the Properties of the Tobacco-Mosaic Virus. Science 81 (1935): Wendell Stanley ( )

10 Stanley s Method for Obtaining Crystalline TMV: Take frozen, ground, infected tobacco leaves (4000 kg); extract twice with disodium phosphate (5000 l) Celite extraction, leaving sparkling clear brown liquid Add sulfuric acid to ph 5. Add ammonium sulfate to 0.4 saturation Refilter precipitate through celite; repeat above step Precipitate with lead subacetate at ph 8 Stanley's crystalline TMV magnified Crystallization with ammonium sulfate at ph 4.5

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12 Félix d Herelle and the Discovery of Bacteriophage

13 The Phage Group Alfred Hershey, Max Delbrück, and Salvador Luria

14 From Physics to Biology Delbrück and Luria at Cold Springs Harbor, 1953

15 Niels Bohr: Life and Light (1932) inspires Max Delbrück to switch from theoretical physics to biology

16 Delbrück D. melanogaster Bridges I consulted with [Calvin Bridges] for quite a bit and tried to learn some Drosophila genetics, and... I didn t make much progress in reading these forbidding-looking papers; every genotype was about a mile long, terrible, and I just didn t get any grasp of it. Max Delbrück

17 Why Phage? Phage replication is where we find the simplest case of duplication of highly complex molecules, under conditions that allow controlled quantitative experiments. Since I started this work I have become more and more convinced of its importance and its great experimental possibilities. Max Delbrück

18 We must be prepared to find a new type of physical law prevailing in [biology]. Or are we to term it a nonphysical, not to say super-physical, law? No. I do not think that. For the new principle that is involved is a genuinely physical one: it is, in my opinion, nothing else than the principle of quantum theory over all.

19 Biology and the Problem of Information Transfer: How was information coded? How did it remain stable during repeated transfers from one cell to another? How was the occasional variation introduced in the information?

20 If the genes are conceived as chemical substances, only one class of compounds need be given to which they can be reckoned as belonging, and that is the proteins in the wider sense, on account of the inexhaustible possibilities for variation which they offer.... The most likely role for the nucleic acids seems to be that of the structuredetermining supporting substance. Swedish cytochemist Torbjörn Caspersson in 1936

21 The Bacteria Eater in Action Bacteriophage as seen under an electron microscope

22 Martha Chase and Alfred Hershey demonstrate conclusively in 1952 that DNA carries the genetic information with their research on phage replication

23 Linus Pauling drawing a molecular structure on a blackboard, 1957

24 There seems to be an epidemic among the physicists, maladia biologica you may call it. George Gamow to Wendell Stanley, 24 February 1947 Gamow catches the malady: working with a model of DNA in the spring of 1954