I’ve recently been preparing some new courses which have given me the opportunity to browse through the literature from the dawn of molecular biology. And in the process I came across a 43 year old paper entitled “Studies of Polynucleotides XCVI. Repair replication of short synthetic DNA’s as catalyzed by DNA polymerase.” by Kleppe and Khorana in the Journal of Molecular Biology. Its an elegant manuscript that describes how DNA polymerase can replicate a DNA strand but only if there is a section of duplex DNA, known a as primer, from which it can start.

So Klepper et.al. started off with a bit of DNA that looked like this:

and after incubating with DNA polymerase ended up with a DNA sequence with the gaps filled in, like so.

Well isn’t that nice?

But the really intriguing bit is the last paragraph of the discussion.

.. the DNA duplex would be denatured to form single strands. This denaturation step would be carried out in the presence of a sufficiently large excess of the two appropriate primers. Upon cooling, one would hope to obtain two structures, each containing the full length of the template strand appropriately complexed with the primer. DNA polymerase will be added to complete the process of repair replication. Two molecules of the original duplex should result. The whole cycle could be repeated, there being added every time a fresh dose of the enzyme. … After every cycle of repair replication, the process of strand separation would have to be repeated. Experiments based on these lines of thought are in progress.

Wow, what a cliff hanger. Kleppe has just described polymerase chain reactions (PCR), the now ubiquitous method for amplifying DNA. But this was 14 years before Kary Mullis (with Saikia as first authur) published the first application of PCR in Science.

But despite the tantalising ending to Kleppe’s paper, nothing else emerges from Khorana’s group to that effect. He never published those experiments. And indeed no one else picked up on the idea until Kary Mullis ran with it.

Its an interesting story that’s been brought up plenty of times before, but having stumbled across the original paper describing the ‘invention’ of PCR and given the big DNA anniversary next week, I thought I’d put it out there again.