The story of Phoebus Levene, one of the mostly invisible grandfathers of nucleic acids

Watson and Crick were the first to describe the structure of the DNA double helix. Their major contribution to science was, at its core, a synthesis of all of the best data available at the time.

The story of Phoebus Levene, one of the mostly invisible grandfathers of nucleic acids

This statement isn’t meant to discount what they did in 1953, but more so to recognize all of the foundational work that preceded them.

1869 - Nuclein (DNA) is discovered - F. Miescher

1912 - The hydrogen bond is proposed - T. S. Moore and T. F. Winmill, Popularized by L. Pauling

1935 - DNA is a macromolecule with a sugar phosphate backbone - P. Levene

1943, 1952 - DNA is the genetic material - Avery-MacLeod-McCarthy, Hershey-Chase

1950 - A and T, G and C are in a 1:1 ratio - E. Chargaff

1952 - DNA is a helix - Rosalind Franklin, she got the math right

1953 - Watson-Crick base pairing - Broomhead, Donahue, Watson, Crick

While all of these pieces were required for the final structure to be determined, the bulk of the basic chemistry was done between 1905 and 1935.

The figure above is the culmination of the life’s work of Phoebus Levene.

He's probably not someone you’ve heard of before.

He was the first to discover that nucleic acids are composed of ribose sugars.

He also determined that these sugars were connected by a phosphate backbone.

And, he eventually figured out that DNA is made of 2-deoxy-D-ribose while RNA is D-ribose.

Oh, he also confirmed the identities of all of the bases: Adenine, Thymine, Guanine, Cytosine and Uracil.

And he's the reason why we call these bases nucleotides!

Pretty mind blowing, right?

This work is summarized in the figure below which displays Levene's 2 dimensional chemical structure for 'Desoxy-ribose nucleic acid.' This structure isn't perfect (Cytosine is labeled as a diphosphate and the chemical composition of the nucleobases is a little off) but it does accurately depict the 5'-3' sugar phosphate backbone of DNA.

Now, the reason why you've never heard of Levene is because he proposed the 'tetranucleotide hypothesis' which stated that DNA was merely a structural molecule composed of 4 repeating nucleotides.

He was certain this meant DNA was too simple to be the carrier of genetic information.

Like everyone else, he believed that proteins were the obvious choice as the genetic material since there are 5 times as many amino acids.

Unfortunately, Levene's hypothesis took the spotlight off of DNA for decades and this has been described as a 'scientific catastrophe' despite Levene getting the basic chemistry and the 2D structure of DNA mostly correct.

So, for Watson and Crick to finally put the 3D puzzle together it took a renewed interest in DNA as the genetic material, Levene's chemistry, the ratio of the bases from Chargaff, (borrowed?) X-ray diffraction data from Franklin, and a couple pints at the Eagle pub in Cambridge.

The rest is (a very disputed) history.


Levene PA, Tipson RS. 1935. The ring structure of thymidine. J. Biol. Chem. DOI:10.1016/S0021-9258(18)75193-4