Francis Crick: I came across an article in Nature about sickle-cell hemoglobin, by Linus Pauling, in which he said it was a molecular
disease. It had been shown quite recently by geneticists that indeed the gene for
it was inherited in a Mendelian manner. I will not go into the details, but it looked
as if it were caused by a single gene. What Linus and his co-workers had shown was
that there was a change in the hemoglobin molecule, so that under electrophoresis
it moved at a different rate. In other words, one of the charge residues had been
changed.
And I remember how excited I was at this idea, because this was the sort of thing
I was very interested in. I was very interested in genes. Here was presumably a gene
product. It looked much the same, as far as one could tell, in many of its properties,
but there clearly had been some change. As a result of that article, when Vernon Ingram
came to join us at the lab, he and I wanted to find out what happened when there was
a mutation in a gene. Did it affect that particular protein which we believed was
controlled by that gene? We did not make any progress on that. We tried working on
lysozymes and various other things, but Vernon received a specimen, I think through
Perutz, of sickle cell anemia hemoglobin, and he was able to show that Linus was right.
There was a change in a single amino acid. Here we had a very dramatic case of a disease
where, if you have two bad copies of the gene, you probably at least in those days
would not live much beyond your teens. And yet it is a change, as we know now, of
just one base pair in the DNA, one amino acid in the protein.
You may ask "how it is possible that a small molecular change can do something which
will kill you?" But you realize that in the red cell, first of all, there are many
copies made of the gene onto the messenger RNAs, so there is amplification there.
But there is amplification before that, because from the fertilized egg there come
many, many red cells. There are an enormous number of red cells being made by a stem
cell, because the cell is dividing, so you have got a lot of red cells in your blood
which carry the hemoglobin. Then the messenger RNAs produce many copies of the molecule.
Thus, in fact, you get a large mass of not very good molecule, even though it is a
very tiny change in the egg and the sperm. Just one or two atoms here and there is
enough to make a change which is potentially lethal.
Nowadays, of course, these ideas are commonplace, but in those days that was not the
case. You may be surprised to know that most people who worked on protein chemistry
wanted to know merely what the composition was. Fred Sanger had just been doing the
sequence of the first protein to be sequenced, which was insulin. Protein biochemists
really had no idea their subject had anything to do with genetics. Those of you who
are in the field may find this absolutely astonishing, because now it is commonplace.
One of the major functions of genes is for each one to code for a particular protein.
That was not known in those days, so this was a very dramatic case. In fact, as a
result of it, Sydney Brenner, Seymour Benzer, and I gave lectures to Fred Sanger's
group on the elements of genetics. It was the first time they realized that they had
to learn something about the subject. Nowadays, of course, all of you who go into
these things learn it right from the beginning and take it as a matter of course.
And it was very much sparked off by this discovery of Linus that sickle cell hemoglobin
was, as he said, a molecular disease.
