Recently I started a Twitter thread highlighting a couple of seminal discoveries in molecular biology going back in the 40’s 50’s #classicpaper. I received many positive feedback and the thread was quite popular. I am of course very pleased but this was also quite unexpected. Unexpected because it’s classic textbook knowledge really, unexpected (but again a pleasant surprise) because I wrongly thought apparently that nobody anymore read old scientific papers.

I certainly did not read all these papers when I was a student but as I am getting older, I have a growing interest in the history of science. The birth of molecular biology is a fascinating golden period from the revelation of the double helix of DNA to the cracking of the genetic code and first glimpses of gene regulation. This thread was inspired by reading ‘She has her mother’s laugh’ by Carl Zimmer, ‘Life’s greatest secret’ by Matthew Cobb, ‘The eighth day of creation’ by Horace Judson, ‘Brave genius’ by Sean B Carroll and ‘Histoire de la Biologie Moléculaire’ by Michel Morange (that is going to be translated in English by Matthew Cobb).

I strongly encourage students to read these books and these seminal papers (unfortunately many of these seminal papers are still under paywall but you know what to do*). Again, this golden age of creative thought and hypothesis-driven research is such an inspiration. The strategies and methodologies created from scratch for almost each experiments, the concepts developed that are still true and central to modern biology, pure joy. As I sometimes said, if time travel was possible I would love to have lived in the 50’s-60’s to witness the birth of Molecular Biology and meet all these fantastic scientists.




1⃣ 1944 Oswald Avery, Colin MacLeod & Maclyn McCarty – DNA, not protein as was commonly believed, is the hereditary material for bacteria, and the cause of bacterial transformation.

2⃣ 1947 André Boivin & Roger Vendrely – a near forgotten 2 pages in French that suggest almost explicitly that DNA –> RNA –> protein.

3⃣ 1952 & 1953 Alexander Dounce – like Boivin & Vendrely, Dounce is one of the first to propose that DNA might serve as a template for the synthesis of RNA, which in turn serves as a template for the synthesis of proteins.

4⃣ 1952 Alfred Hershey & Martha Chase – They confirmed that DNA was the molecule of heredity a.k.a as the blender experiment. (However as Matthew Cobb told me, After the experiment, after the double helix, Hershey still thought protein played a role. See this recount for example).

5⃣ 1953 The structure of DNA – Watson & Crick, Franklin & Gosling, Wilkins Stokes Wilson.

8XHZX(source image)

6⃣ 1956 & 1958 Francis Crick – The Central Dogma: once ‘information’ is passed into protein it cannot get out again.


7⃣ To read a clear explanation of the 2 unrelated hypotheses ‘The Central Dogma’ and ‘DNA -> RNA -> Proteins’, have a look at Dan Graur blog post.

8⃣ 1958 Francis Crick – The adaptor hypothesis (in On protein Synthesis): to explain how information encoded in DNA is used to specify the amino acid sequence of proteins.

9⃣ 1958 Mahlon Hoagland – Discovery of the adaptors = soluble RNAs a.k.a. tRNA.

1⃣0⃣ 1957 Vernon Ingram – The first demonstration that the abnormal haemoglobin in sickle cell anaemia patients is caused by an alteration in one amino acid.

1⃣1⃣ 1958 Matthew Meselson and Franklin W. Stahl – experimental proof of Semi-Conservative DNA replication.

1⃣2⃣ 1959 Pardee, Jacob & Monod – The PaJaMo experiment that supported the hypothesis that a molecule mediated the production of proteins from DNA (cytoplasmic messenger).

1⃣3⃣ 1961 Jacob & Monod – The fundamental basis of gene regulation, one of the most influential paper in the history of modern biology (& I am not saying that because Jacob & Monod were French).  And yes RNA was already proposed by Jacob and Monod in 1961 to control the operon.


1⃣4⃣ 1961 Brenner, Jacob, Meselson Gros, Hiatt, Gilbert, Kurland, Risebrough, Watson The discovery of messenger RNA (mRNA).

1⃣5⃣ For an historical point of view of the discovery of mRNA, see also this great recount by Matthew Cobb.


1⃣6⃣ 1961 Marshall W. Nirenberg & J. Heinrich Matthaei – A poly-U RNA was translated into polyphenylalanine in a cell-free system. This experiment provided the initial clue to breaking the genetic code. See also the didicated NIH web site.

1⃣6⃣ bis 1965 Marshall W. Nirenberg Philip Leder – The template activities of 26 additional trinucleotides are described in this paper. (source image)


1⃣7⃣ 1961 Crick, Barnett, Brenner & Watts-Tobin – The existing knowledge in 1961 & the experimental procedures were certainly not sufficient to allow anyone to deduce the general nature of the genetic code but they nearly solved the riddle.

1⃣8⃣ 1965 Margarita Salas – The first experimental results indicating that the direction of reading of the genetic message is from the 5’ to the 3’ end  (see also My scientific life by Margarita Salas in 2016).

1⃣9⃣ 1964 K. Marcker & F. Sanger and 1966 B. F. C. Clark & K. A. Marcker  – A role for methionine in polypeptide chain initiation.

2⃣0⃣ 1966 Francis Crick – The Wobble hypothesis. A visionary Crick again explains why multiple codons can code for a single amino acid.

2⃣1⃣ 1967 Brenner – The last of the 64-Triplet Genetic Code is cracked.

2⃣1⃣ bis 1964 Allfrey Faulkner Mirsky –  Acetylation & methylation of histones & their possible role in the regulation of RNA synthesis.

2⃣2⃣ 1969 Britten & Davidson – Like the Monod & Jacob paper in 1961, a very influential paper on gene regulation. Their theory stated the hypothesis that repetitive non-coding sequences are at the core of genetic regulation.

2⃣3⃣ 1968 Karin Ippen-Ihler – Studies using the lac operon identified the promoter as a cis controlling element for gene transcription.


(source image)

2⃣4⃣ 1969 Bob Roeder & William J. Rutter – the discovery of 3 chromatographically separable forms of eukaryotic RNA polymerase from sea urchin embryos (I, II and III).


(Source image)

2⃣5⃣ 1970 Kedinger, Gniazdowski, Mandel, Gissinger & Chambon – Pierre Chambon also isolated 2 activities from calf thymus, Pol A (Pol I) & Pol B (Pol II), of which only Pol B was inhibited by the Amanita toxin α-amanitin.


2⃣6⃣ 1974 Roger Kornberg – The organizing principle of the nucleosome, a histone octamer, and its mode of interaction with DNA. Here and here.

2⃣7⃣ 1975 P. Oudet, M. Gross-Bellard, & P. Chambon – The first electron microscopy of reconstituted histone–DNA complexes a.k.a. beads on a string.


2⃣8⃣ 1977 several papers reporting the discovery of interrupted ‘split’ genes a.k.a introns. Berget Sharp, Chow, Breathnach Chambon, Klessig, Dunn Hassell, Lewis.


2⃣9⃣ 1980 Corden Chambon – One of the first comparisons of promoter sequences from efficiently transcribed protein-coding genes.

3⃣0⃣ 1981 Julian Banerji Sandro Rusconi & Walter Schaffner – Discovery of enhancers (see also this historical perspective by Walter Schaffner).


See also Cell Annotated Classics, PNAS Classics, Nature Milestones in gene expression,



* If you really don’t know what to do, click here.

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