Classical Protein Chemistry in a World of
      Slicing and Splicing

   The explosive development of DNA.recombinant technology
has made it possible to carry out large-scale production of
a number of medically and industrially important proteins
and peptides.  At the same time, new methods in protein chemistry
have appeared which should increasingly permit the efficient
isolation,  structure determination, and synthesis of large
and small polypeptides.

   Before much of anything can be done with a protein,
it must be isolated in pure form and its covalent structure
must be determined.  The standard methods of protein isolation
have been enormously facilitated over the past few years by
the development of the technique of affinity chromatography
using columns to which have been bound either substrate analogs
or specific antibodies.  In many cases,  affinity chromatography
can lead directly from the crude source of a protein to homo-
geneous material in a single step.  At this point, we may
capitalize on still another exciting development in modern
protein chemistry - microsequencing as carried out strikingly
by Hunkapiller and Hood at Cal Tech.  Their improvements in
the original method of Edman have led to the commercial avail-
ability of equipment that even novices can use with considerable
success and,  most important,  on very small samples of material,
frequently less that 50 picomoles.  Having determined the amino-
acid sequence of a protein and the nature of any non-aminoacid
components attached to side chains,  the protein can then be
turned over to our crystallographic experts -- individuals
such as Joe Kraut and his colleagues around the world who
employ the new developments in heavy atom tagging and, with the
availability of sophisticated equipment that efficiently feeds
diffraction data into intelligent computers, can produce three-
dimensional representations with outstanding speed.

   My own particular interest over quite a few years has
been the relation between the primary structures of protein
molucules and their three-dimensional structure.   Most of us
are convinced by this time,  that the three-dimensional structure
is completely determined by the primary structure and that
the folding process goes spontaneously.

   Extensions of the folding problem have become particularly
important in the last ten years or so because of interest in
such possibilities as the preparation of totally synthetic


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vaccines.  Can one look at the structure of a protein, preferably
in three dimensions, and select areas on the surface which might
be expected to have a strong tendency to fold properly even
when chopped out of the total structure?   I will describe to
you a few experiments relating to this biological problem
in a few moments.  My own interest began with some work that
was carried out with Ruth Arnon and Michael Sela at the Weizmann
Institute on the so-called lysozyme loop -- a small disulphide-
stabilized extension on the enzyme.  When this loop was prepared
synthetically.and attached to a non-immunogenic carrier, injectior
into animals produced antibodies which did indeed recognize
the parent enzyme molecule.  One might say that this material
constituted a synthetic vaccine against the lysozyme molecule.
Through the activity now going on in a variety of laboratories --
1 might mention the Scripps Clinic in La Jolla, some work from
which will be described to us by Dr. Getsoff; the Weizmann
Institute in Rehovot, Israel;  and our own laboratories at the
NIH -- we became interested in the ability of various peptide
fragments of proteins to fold up into the conformations that
they assume when part of the native protein.  Affinity chromo-
tographic methods were employed to isolate antibodies against
various parts of molecules, which could then be used to study
the "foldability" fragments.

   Let me conclude by mentioning a few bits of relatively
recent protein chemistry that suggest that a good deal of
methodology for the specific modification of proteins and
partial or total synthesis is already available.  Homandberg
and Laskowski demonstrated, in the late 'IO's, that protein
fragments could,  following modification of the solvent to
include high levels of a nonaqueous substance such as glycerol,
be proteolytically reunited to produce the original parent
chain.       These stitching procedures are of considerable
potential value since they provide a way of joining portions
of protein chains that fall within the useful limits of the
Merrifield solid-phase technique.

Professional Interests:

   Protein Chemistry:  synthesis,  structure-function, folding,
isolation,  and chemistry of the interferon molecule.

Awards and Personal Interests:

   Interesting punctuation points in my own career have been
a Nobel Prize in Chemistry in 1972, a long-standing connection
with the Weizmann Institute of Science in Israel, and an on-going
fascination with (and I might say frustration with) the broad
problem of human rights.