Both Crick and Watson focused on virus structure in the mid-1950s because studying viruses, in particular Tobacco Mosaic Virus
(TMV) and related plant viruses, allowed them to investigate the structure and function of RNA (ribonucleic acid), which
together with regular repeating units of protein makes up the molecules of which TMV consists. As the single-stranded companion
molecule to DNA, RNA held obvious interest for Crick and Watson in their attempt to understand the way in which RNA specifies
the synthesis of proteins, triggered whenever TMV infects a host cell.
In laying out experimental details about the structure of TMV, Watson confirmed Rosalind Franklin's finding that the strands
of RNA bound the virus' hollow core: "The localization of the RNA within a central core is now a solid fact."
Item is handwritten.
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1955-03-03 (March 3, 1955)
Watson, James D.
Original Repository: Wellcome Library for the History and Understanding of Medicine. Francis Harry Compton Crick Papers
To start with, I warn you to accept this letter with marked scepticism [sic]. For there is a good chance that everything it
states will turn out to be either wrong or at best trivial. They concern our favorite virus TMV.
The localization of the RNA within a central core is now a solid fact. The problem now is to determine its structure when
within TMV. Naturally x-rays are the only hope so let us look at the Fourier which Don Caspar believes most probable. The
sign combination is plus, minus, minus plus minus plus minus. It produces a [diagrams numbered 1 and 2] peak at 22 angstroms
which must be the phosphates. The only other Fourier which might be right derives from the plus minus plus minus plus minus
plus combination and I believe is the one found by Rosy Don does not like it since it fails to converge [special character,
around or about] 80 angstroms and seems [line from "seems" in text to the following, moderately phony -- this is important]
to have too little mass within a 40 angstrom diameter core for the RNA. We thus base all our speculations upon the correctness
of number 1.
If all the phosphates are located at a constant radius, then it seems desirable to see if it can interact in a systematic
manner with the protein shell. We first of all remember that the TMV helix can arbitrarily be considered a one stranded helix,
or a 12 stranded intertwined beast (or a similar number such as 10 or 14) it just depends how we want to link up the protein
monomers. We must then decide whether all of the nucleotides are equivalent. Of course to start with, we decide they are.
[END PAGE ONE]
[BEGIN PAGE TWO]
improbable a one stranded RNA rope with 22 angstrom pitch and turns our thoughts toward many stranded structures -- say 12
To judge its plausibility we refer to the MW of TMV RNA. It starts out at 2,500,000 (Sinsheineir [?]) but rapidly falls to
something (Cohen and Stanley JBC 144 (1942) around 300,000. Recently Norman Simons has reinvestigated RNA from TMV using Kylene
Sulphorate to get it out. The sedimentation constant is 134 I times 5 and the D20 about 2 times 10 to the negative 7 power.
The MW seems to be at 330,000 and may be greater as the material is definitely unstable and not too homogenous. Notice that
[mathematical equation, see Lister Hill?] -- Also that this is the material which gives us our mediocre x-ray pictures, which
at times I thought to be DNA like. It cannot be a simple single chain since Markham (Knight also!) finds one end group [special
character unidentified] 50 -- And that its more stable (Cohen and Stanley) at pH 4 than at 7. Of course we detest branches
but can't almost everything be understandable if RNA were not RNA but the following beast.
Thus the anhydride revived but in a new form. We have to postulate that its completely unstable when its protein coat is removed
and that the weakest link is the P-O-P pyrophosphate bond. However rarely a P-O-C bond goes instead and Roy Markham's
end groups arise.
The idea has two main merits. First it can be checked by isolating the RNA in the presence of H2O18 We should find one O18
atom per pair of P atoms This experiment will take time but is already being planned and we may have an answer in 6-8 weeks.
It will take time to get the TMV, etc.
[diagram on left side of page]
[END PAGE TWO]
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Secondly the structure is surprisingly neat crystallographically. It almost seems a natural and so I believe we must consider
the posibility [sic] of its existing some place even if the virus expt gives a negative result. It can be built with DNA --
of course the bases are not paired but maybe during replication it might exist. I urge you to build it and see if your reactions
compare with mine.
It naturally intrigues me for if true it would make RNA a high energy beast. I would guess that RNA is not a passive template
(no high turnover expts glare at us) and that the attempts of Leslie and I to thrust a simple template role was bound to failure.
Right now I feel, that some serious thinking about biochemical mechanisms is in order. However I can't yet push myself
to do this until the O18 result comes in. I have no ideas at all about the base arrangement or about its replication but I
suspect something should be seen. And maybe the similarity to co-enzymes is not coincidental e.g. DPN. If any of their speculations
are true, then the whole story is going to be more complex than originally thought but still nice in that it would combine
the biochemical synthesis with molecular model approach.
The hypothesis would simply explain our bad x-ray pictures since what we are looking at is a disorganized double helix devoid
of pairing. It points to the Plant Viruses as the "Secret of Life" and makes even more desirable a solution of their
structure. At present I think the most fruitful thing is to obtain a Fourier from PVX. Is Rosie doing anything along these
lines? Are you interested. Now is the growing time for plant viruses and it would be splendid if Roy Markham could be seduced
to obtaining you large amounts. We shall try to obtain some in Berkeley and I shall
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bring some with me to Cambridge in early July. However I think its risky to count on transatlantic sources. The x-ray tubes
here are too weak to accomplish anything worthwhile. Sturtivant is not a man (technician!!) to be pushed.
These ideas of mine are admittedly wild. However I have a strong feeling that our correct thoughts are getting nowhere and
that a radical idea will be necessary before RNA begins to make sense. I think they must come from good chemical intuition
and on this score I feel particularly weak. Nevertheless we are badly in need of hypotheses (possibly even published) in order
to push additional people to think along these lines. At present I have the feeling I am the only person (with the possible
exception of you) who is seriously attempting to shock the bloody structure. I do not like to be this exclusive and unfortunately
the coding approach only makes me feel more isolated. You complain of the isolation of Cambridge. At least there no one expects
you to solve the problem. Here they do, but offer no help.
I am flying East in about 10 days for a meeting in Baltimore. I shall probably remain there for 2-3 weeks since until the
O18 expt can be done, there is little I can do here except to become impatient.
Regards to all. Please tell them that my lack of correspondence does not reflect a lack of interest. Since I shall be over
in about 3 1/2 months, gossip can wait until then. Also nothing of interest happens in this social desert. So I would appreciate
a gossip letter from Odile
Mail will reach me here if it arrives before March 11th, otherwise write me in care of Alex Rich