Francis Harry Compton Crick (June 1916 – July 2004) was an English ...
> "Biologists should not deceive themselves with the thought that s...
James Watson and Francis Crick worked together (along with Rosalind...
> "By contrast the most significant thing about proteins is that th...
Some more background on amino acids: https://en.wikipedia.org/wiki/...
> "This family likeness between the same protein molecules from dif...
> "My own thinking (and that of many of my colleagues) is based on...
ON
PROTEIN
SYNTHESIS
By
F.
H.
C.:CRICK
Medical
Research
Council
Unit
for
the
Study
of
Molecular
Biology,
Cavendish
Laboratory,
Cambridge
I.
INTRODUCTION
Protein
synthesis
is
a
large
subject
in
a
state
of
rapid
development.
To
cover
it
completely
in
this
article
would
be
impossible.
I
have
therefore
deliber-
ately
limited
myself
here
to
presenting
a
broad
general
view
of
the
problem,
emphasizing
in
particular
well-established
facts
which
require
explanation,
and
only
selecting
from
recent
work
those
experiments
whose
implications
seem
likély
to
be
of
lasting
significance.
Much
very
recent
work,
often
of
great
interest,
has
been
omitted
because
its
implications
are
not
clear.
I
have
also
tried
to
relate
the
problem
to
the
other
central
problems
of
molecular
biologythose
of
gene
action
and
nucleic
acid
synthesis.
In
short,
I
have
written
for
the
biologist
rather
than
the
biochemist,
the
general
reader
rather
than
the
specialist.
More
technical
reviews
have
appeared
recently
by
Borsook
(1956),
Spiegelman
(1957),
and
Simkin
&
Work
(19576
and
this
Symposium).
The
importance
of
proteins
It
is
an
essential
feature
of
my
argument
that
in
biology
proteins
are
uniquely
important.
They
are
not
to
be
classed
with
polysaccharides,
for
example,
which
by
comparison
play
a
very
minor
role.
Their
nearest
rivals
.
are
the
nucleic
acids.
Watson
said
to
me,
a
few
years
ago,
The
most
significant
thing
about
the
nucleic
acids
is
that
we
dont
know
what
they
do.
By
contrast
the
most
significant
thing
about
proteins
is
that
they
can
do
almost
anything.
In
animals
proteins
are
used
for
structural
purposes,
but
this
is
not
their
main
role,
and
indeed
in
plants
this
job
is
usually
done
by
polysaccharides.
The
main
function
of
proteins
is
to
act
as
enzymes,
Almost
all
chemical
reactions
in
living
systems
are
catalysed
by
enzymes,
and
all
known
enzymes
are
proteins.
It
is
at
first
sight
paradoxical
that
it
is
probably
easier
for
an
organism
to
produce
a
new
protein
than
to
produce
a
new
small
molecule,
since
to
produce
a
new
small
molecule
one
or
more
new
proteins
will
be
required
in
any
case
to
catalyse
the
reactions.
I
shall
also
argue
that
the
main
function
of the
genetic
material
is
to
control
(not
necessarily
directly)
the
synthesis
of
proteins.
There
is
a
little
direct
evidence
to
support
this,
but
to
my
mind
the
psychological
drive
behind
this
hypothesis
is
at
the
moment
independent
of
such
evidence.
PROTEIN
SYNTHESIS
139
Once
the
central
and
unique
role
of
proteins
is
admitted
there
seems
little
point
in
genes
doing
anything
else.
Although
proteins
can
act
in
so
many
different
ways,
the
way
in
which
they
are
synthesized
is
probably
uniform
and
rather
simple,
and
this
fits
in
with
the
modern
view
that
gene
action,
being
based
upon
the
nucleic
acids,
is
also
likely
to
be
uniform
and
rather
simple.
Biologists
should
not
deceive
themselves
with
the
thought
that
some
new
class
of
biological
molecules,
of
comparable
importance
to
the
proteins,
remains
to
be
discovered.
This
seems
highly
unlikely.
In
the
protein
molecule
Nature
has
devised
a
unique
instrument
in
which
an
underlying
simplicity
is
used
to
express
great
subtlety
and
versatility;
it
is
impossible
to
see
molecular
biology
in
proper
perspective
until
this
peculiar
combi-
nation
of
virtues
has
been
clearly
grasped.
Il.
THE
PROBLEM
Elementary
facts
about
proteins
(1)
Composition.
Simple
(unconjugated)
proteins
break
down
on
hydro-
lysis
to
amino
acids.
There
is
good
evidence
that
in
a
native
protein
the
-
amino
acids
are
condensed
into
long
polypeptide
chains.
A
typical
protein,
of
molecular
weight
about
25,000,
will
contain
some
230
residues
joined
end-to-end
to
form
a
single
polypeptide
chain.
Two
points
are
important.
First,
the
actual
chemical
step
required
to
form
the
covalent
bonds
of
the
protein
is
always
the
same,
irrespective
of
the
amino
acid
concerned,
namely
the
formation
of
the
peptide
link
with
the
elimination
of
water.
Apart
from
minor
exceptions
(such
as
SS
links
and,
sometimes,
the
attachment
of
a
prosthetic
group)
all
the
covalent
links
within
a
protein
are
formed
in
this
way.
Covalently,
therefore,
a
protein
is
to
a
large
extent
a
linear
molecule
(in
the
topological
sense)
and
there
is
little
evidence
that
the
backbone
is
ever
branched.
From
this
point
of
view
the
cross-linking
by
SS
bridges
is
looked
upon
as
a
secondary
process.
The
second
important
pointand
I
am
surprised
that
it
is
not
remarked
more
oftenis
that
only
about
twenty
different
kinds
of
amino
acids
occur
in
proteins,
and
that
these
same
twenty
occur,
broadly
speaking,
in
all
proteins,
of
whatever
originanimal,
plant
or
micro-organism.
Of
course
not
every
protein
contains
every
amino
acidthe
amino
acid
tryptophan,
which
is
one
of
the
rarer
ones,
does
not
occur
in
insulin,
for
example
but
the
majority
of
proteins
contain
at
least
one
of
each
of
the
twenty
amino
acids.
In
addition
all
these
twenty
amino
acids
(apart
from
glycine)
have
the
L
configuration
when
they
occur
in
genuine
proteins.
There
are
a
few
proteins
which
contain
amino
acids
not
found
else-
140
PROTEIN
SYNTHESIS
wherethe
hydroxyproline
of
collagen
is
a
good
examplebut
in
all
such
cases
it
is
possible
to
argue
that
their
presence
is
due
to
a
modification
of
the
protein
after
it
has
been
synthesized
or
to
some
other
abnormality,
In
Table
1,
I
have
listed
the
standard
twenty
amino
acids
believed
to
be
of
universal
occurrence
and
also,
in
the
last
column,
some
of the
exceptional
ones.
The
assignment
given
in
Table
1
might
not
be
agreed
by
everyone,
Table
1
The
magic
twenty
amino
acids
found
universally
in
in
proteins
-
~
Other
amino
acids
found
in
proteins
Glycine
Asparagine
Hydroxyproline*
Alanine
Glutamine
Hydroxylysine
Valine
Aspartic
acid
Phosphoserine
|
Leucine
Glutamic
acid
Diaminopimelic
acid
Isoleucine
Arginine
Thyroxine
and
related
molecules
Proline*
Lysine
Phenylalanine
Histidine
Cystinet
Tyrosine
Tryptophan
Serine
Cysteinet
Threonine
Methionine
*
These
are,
of
course,
imino
acids.
This
distinction
is
not
made
in
the
text.
t
This
classification
implies
that
all
the
cystine
found
in
proteins
is
formed
by
the
joining
together
of
two
cysteine
molecules.
as
the
evidence
is
incomplete,
but
more
agreement
could
be
found
for
this
version
than
for
any
other.
Curiously
enough
this
point
is
slurred
over
by
almost
all
biochemical
textbooks,
the
authors
of
which
give
the
impression
that
they
are
trying
to
include
as
many
amino
acids
in
their
lists
as
they
can,
without
bothering
to
distinguish
between
the
magic
twenty
and
the
others.
(But
see
a
recent
detailed
review
by
Synge,
1957.)
(2)
Homogeneity.
Not
only
is
the
composition
of
a
given
protein
fixed,
.
but
we
have
every
reason
to
believe
that
the
exact
order
of
the
amino
acid
residues
along
the
polypeptide
chains
is
also
rigidly
determined:
that
each
molecule
of
haemoglobin
in
your
blood,
for
example,
has
exactly
the
same
sequence
of
amino
acids
as
every
other
one.
This
is
clearly
an
overstate-
ment;
the
mechanism
must
make
mistakes
sometimes,
and,
as
we
shall
see,
there
are
also
interesting
exceptions
which
are
under
genetic
control.
Moreover,
it
is
quite
easy,
in
extracting
a
protein,
to
modify
some
of
the
molecules
slightly
without
affecting
the
others,
so
that
the
pure
protein
may
appear
heterogeneous.
The
exact
amount
of
microheterogeneity
of
proteins
is
controversial
(see
the
review
by
Steinberg
&
Mihalyi,
1957),
but
this
should
not
blind
one
to
the
astonishing
degree
of
homogeneity
of
most
proteins.*
(3)
Structure.
In
a
native
globular
protein
the
polypeptide
chain
is
not
*
The
y-globulins
and
other
antibody
molecules
are
exceptions
to
these
generalizations,
They
are
probably
heterogeneous
in
folding
and
possibly
to
some
extent
in
composition,
PROTEIN
SYNTHESIS
14!
fully
extended
but
is
thrown
into
folds
and
superfolds,
maintained
by
weak
physical
bonds,
and
in
some
cases
by
covalent
SS
links
and
possibly
some
others.
This
folding
is
also
thought
to
be
at
least
broadly
the
same
for
each
copy
of
a
particular
protein,
since
many
proteins
can
be
crystallized,
though
the
evidence
for
perfect
homogeneity
of
folding
is
perhaps
rather
weak.*
As
is
well
known,
if
this
folding
is
destroyed
by
heat
or
other
methods
the
protein
is
said
to
be
denatured.
The
biological
properties
of
most
proteins,
especially
the
catalytic
action
of
enzymes,
must
depend
on
the
exact
spatial
arrangement
of
certain
side-groups
on
the
surface
of
the
protein,
and
altering
this
arrangement
by
unfolding
the
polypeptide
chains
will
destroy
the
biological
specificity
of
the
proteins.
(4)
Amino
acid
requirements.
If
one
of
the
twenty
amino
acids
is
supplied
toa
cell
it
can
be
incorporated
into
proteins;
amino
acids
are
certainly
protein
precursors,
The
only
exceptions
are
amino
acids
like
hydroxyproline,
which
are
not
among
the
magic
twenty.
The
utilization
of
peptides
is
controversial
but
the
balance
of
evidence
is
against
the
occurrence
of
peptide
inter=
mediates.
(See
the
discussion
by
Simkin
&
Work,
this
Symposium.)
»
If,
for
some
reason,
one
of
the
twenty
amino
acids
is
not
available
to
the
organism,
protein
synthesis
stops.
Moreover,
thé
continued
synthesis
of
those
parts
of
the
protein
molecules
which
do
not
contain
that
amino
acid
appears
not
to
take
place.
This
can
be
demonstrated
particularly
clearly
in
bacteria,
but
it
is
also
true
of
higher
animals.
If
a
meal
is
provided
that
lacks
an
essential
amino
acid
it
is
no
use
trying
to
make
up
for
this
deficiency
by
providing
it
a
few
hours
later.
Very
little
is
known
about
the
accuracy
with
which
the
amino
acids
are
selected.
One
would
certainly
expect,
for
example,
that
the
mechanism
would
occasionally
put
a
valine
into
an
isoleucine
site,
but
exactly
how
often
this
occurs
is
not
known.
The
impression
one
gets
from
the
rather
meagre
facts
at
present
available
is
that
mistakes
occur
rather infrequently.
In
recent
years
it
has
been
possible
to
introduce
amino
acid
analogues
into
proteins
by
supplying
the
analogue
under
circumstances
in
which
the
amino
acid
itself
is
not
easily
available
(see
the
review
by
Kamin
&
Handler,
1957).
For
example
in
Escherichia
coli
fluorophenylalanine
has
been
in-
corporated
in
place
of
phenylalanine
and
tyrosine
(Munier
&
Cohen,
1956)
and
it
has
even
proved
possible
to
replace
completely
the
sulphur-containing
amino
acid
methionine
by
its
selenium
analogue
(Cohen
&
Cowie,
1957).
Of
the
enzymes
produced
by
the
cell
in
these
various
ways
some
were
active
and
some
were
inactive,
as
might
have
been
expected.
(5)
Contrast
with
polysaccharides.
It
is
useful
at
this
point
to
contrast
proteins
with
polysaccharides
to
underline
the
differences
between
them.
*
See
previous
footnote.
142
PROTEIN
SYNTHESIS
(1
do
not
include
nucleic
acids
among
the
polysaccharides.)
Polysac-
charides,
too,
are
polymers,
but
each
one
is
constructed
from
one,
or
at
the
most
only
about
half-a-dozen
kinds
of
monomer.
Nevertheless
many
different
monomers
are
found
throughout
Nature,
some
occurring
here,
some
there.
There
is
no
standard
set
of
monomers
which
is
always
used,
as
there
is
for
proteins.
Then
polysaccharides
are
polydisperseat
least
so
far
no
monodisperse
one
has
been
foundand
the
order
of
their
monomers
is
unlikely
to
be
rigidly
controlled,
except
in
some
very
simple
manner.
Finally
in
those
cases
which
have
been
carefully
studied,
such
as
starch,
glycogen
and
hyaluronic
acid,
it
has
been
found
that
the
polymerization
is
carried
out
in
a
straightforward
way
by
enzymes.
(6)
The
genetics
and
taxonomy
of
proteins.
It
is
instructive
to
compare
your
own
haemoglobin
with
that
of a
horse.
Both
molecules
are
indis-
tinguishable
in
size.
Both
have
similar
amino
acid
compositions;
similar
but
not
identical.
They
differ
a
little
electrophoretically,
form
different
crystals,
and
have
slightly
different
ends
to
their
polypeptide
chains.
All
these
facts
are
compatible
with
their
polypeptide
chains
having
similar
amino
acid
sequences,
but
with
just a
few
changes
here
and
there.
.
This
family
likeness
between
the
same
protein
molecules
from
different
species
is
the
rule
rather
than
the
exception.
It
has
been
found
in
almost
every
case
in
which
it
has
been
looked
for.
One
of
the
best-studied
examples
is
that
of
insulin,
by
Sanger
and
his
co-workers
(Brown,
Sanger
&
Kitai,
1955;
Harris,
Sanger
&
Naughton,
1956),
who
have
worked
out
the
complete
amino
acid
sequences
for
five
different
species,
only
two
of
which
(pig
and
whale)
are
the
same.
Interestingly
enough
the
differences
are
all
located
in
one
small
segment
of
one
of
the
two
chains.
Biologists
should
realize
that
before
long
we
shall
have
a
subject
which
might
be
called
protein
taxonomythe
study
of
the
amino
acid
sequences
of
the
proteins
of
an
organism
and
the
comparison
of
them
between
species.
It
can
be
argued
that
these
sequences
are
the
most
delicate
expression
possible
of
the
phenotype
of
an
organism
and
that
vast
amounts
of
evolutionary
information
may
be
hidden
away
within
them.
There
is,
however,
nothing
in
the
evidence
presented
so
far
to
prove
that
these
differences
between
species
are
under
the
control
of
Mendelian
genes.
It
could
be
argued
that
they
were
transmitted
cytoplasmically
through
the
egg.
Onthe
other
hand,
there
is
much
evidence
that
genes
do
affect
enzymes,
especially
from
work
on
micro-organisms
such
as
Neurospora
(see
Wagner
&
Mitchell,
1955).
The
famous
one
geneone
enzyme
hypothesis
(Beadle,
1945)
expresses
this
fact,
although
its
truth
is
controversial
(personally
I
believe
it
to
be
largely
correct).
However,
in
none
of
these
cases
has
the
protein
(the
enzyme,
that
is)
ever
been
obtained
pure.
PROTEIN
SYNTHESIS
143
There
are
a
few
cases
where
a
Mendelian
gene
has
been
shown
un-
ambiguously
to
alter
a
protein,
the
most
famous
being
that
of
human
sickle-
cell-anaemia
haemoglobin,
which
differs
electrophoretically
from
normal
adult
haemoglobin,
as
was
discovered
by
Pauling
and
his
co-workers
(1949).
Until
recently
it
could
have
been
argued
that
this
was
perhaps
not
due
to
a
change
in
amino
acid
sequence,
but
only
to
a
change
in
the
folding.
That
the
gene
does
in
fact
alter
the
amino
acid
sequence
has
now
been
con-
clusively
shown
by
my
colleague,
Dr
Vernon
Ingram.
The
difference
is
due
to
a
valine
residue
occurring
in
the
place
of
a
glutamic
acid
one,
and
Ingram
has
suggestive
evidence
that
this
is
the
only
change
(Ingram,
1956,
1957).
It
may
surprise
the
reader
that
the
alteration
of
one
amino
acid
out
of a
total
of
about
300
can
produce
a
molecule
which
(when
homozygous)
is
usually
lethal
before
adult
life
but,
for
my
part,
Ingram
8
result
is
just
what
I
expected.
:
2
ey
ER
The
nature
of
protein
synthesis
The
basic
dilemma
of
protein
synthesis
has
been
realized
by
many
ny
peopie,
but
it
has
been
particularly
aptly
expressed
by
Dr
A.
L.
Dounce
(1956):
My
interest
in
templates,
and
the
conviction of
their
necessity,
originated
from
a
question
asked
me
on
my
Ph.D.
oral
examination
by
Professor
J.
B.
Sumner.
He
enquired
how
I
thought
proteins
might
be
synthesized.
I
gave
what
seemed
the
obvious
answer,
namely,
that
enzymes
must
be
responsible.
Professor
Sumner
then
asked
me
the
chemical
nature
of
enzymes,
and
when
I
answered
.that
enzymes
were
proteins
or
contained
proteins
as
essential
components,
he
asked
whether
these
enzyme
proteins
were
synthesized
by
other
enzymes
and
so
on
ad
infinitum.
The
dilemma
remained
in
my
mind,
causing
me
to
look
for
possible
solutions
that
would
be
acceptable,
at
least
from
the
standpoint
of
logic.
The
dilemma,
of
course,
involves
the
specificity
of
the
protein
molecule,
which
doubtless
depends
to
a
considerable
degree
on
the
sequence
of
amino
acids
in
the
peptide
chains
of
the
protein.
The
problem
is
to
find
a
reasonably
simple
mechanism
that
could
account
for
specific
sequences
without
demanding
the
presence
of
an
ever-increasing
number
of
new
specific
enzymes
for
the
synthesis
of
each
new
protein
molecule.
It
is
thus
clear
that
the
synthesis
of
proteins
must
be
radically
different
from
the
synthesis
of
polysaccharides,
lipids,
co-enzymes
and
other
small
molecules;
that
it
must
be
relatively
simple,
and
to
a
considerable
extent
uniform
throughout
Nature;
that
it
must
be
highly
specific,
making
few
mistakes;
and
that
in
all
probability
it
must
be
controlled
at
not
too
many
removes
by
the
genetic
material
of
the
organism.
The
essence
of
the
problem
A
systematic
discussion
of
our
present
knowledge
of
protein
synthesis
could
usefully
be
set
out
under
three
headings,
each
dealing
with
a
flux:
144
PROTEIN
SYNTHESIS
the
flow
of
energy,
the
flow
of
matter,
and
the
flow
of
information.
I
shall
not
discuss
the
first
of
these
here.
I
shall
have
something
to
say
about
the
second,
but
I
shall
particularly
emphasize
the
thirdthe
flow
of
information.
By
information
I
mean
the
specification
of
the
amino
acid
sequence
of
the
protein.
It
is
conventional
at
the
moment
to
consider
separately
the
synthesis
of
the
polypeptide
chain
and
its
folding.
It
is
of
course
possible
that
there
is
a
special
mechanism
for
folding
up
the
chain,
but
the
more
likely
hypothesis
is
that
the
folding
is
simply
a
function
of
the
order
of
the
amino
acids,
provided
it
takes
place
as
the
newly
formed
chain
comes
off
the
template.
I
think
myself
that
this
latter
idea
may
well
be
correct,
though
I
would
not
be
surprised
if
exceptions
existed,
especially
the
y-globulins
and
the
adaptive
enzymes.
Our
basic
handicap
at
the
moment
is
that
we
have
no
easy
and
precise
technique
with
which
to
study
how
proteins
are
folded,
whereas
we
can
at
least
make
some
experimental
approach
to
amino
acid
sequences.
For
this
reason,
if
for
no
other,
I
shall
ignore
folding
in
what
follows
and
concentrate
|
on
the
determination
of
sequences.
It
is
as
well
to
realize,
however,
that
the
idea
that
the
two
processes
can
be
considered
separately
is
in
itself
an
assumption.
The
actual
chemical
step
by
which
any
two
amino
acids
(or
activated
amino
acids)
are
joined
together
is
probably
always
the
same,
and
may
well
not
differ
significantly
from
any
other
biological
condensation.
The
unique
feature
of
protein
synthesis
is
that
only
a
single
standard
set
of
twenty
amino
acids
can
be
incorporated,
and
that
for
any
particular
protein
the
amino
acids
must
be
joined
up
in
the
right
order.
It
is
this
problem,
the
problem
of
sequentialization,
which
is
the
crux
of
the
matter,
though
it
is
obviously
important
to
discover
the
exact
chemical
steps
which
lead
up
to
and
permit
the
crucial
act
of
sequentialization,
As
in
even
a
small
bacterial
cell
there
are
probably
a
thousand
different
kinds
of
protein,
each
containing
some
hundreds
of
amino
acids
in
its
own
rigidly
determined
sequence,
the
amount
of
hereditary
information
required
for
sequentialization
is
quite
considerable.
HI.
RECENT
EXPERIMENTAL
WORK
The
role
of
the
nucleic
acids
It
is
widely
believed
(though
not
by
every
one)
that
the
nucleic
acids
are
in
some
way
responsible
for
the
control
of
protein
synthesis,
either
directly
or
indirectly.
The
actual
evidence
for
this
is
rather
meagre.
In
the
case
of
deoxyribonucleic
acid
(DNA)
it
rests
partly
on
the
T-even
bacteriophages,
since
it
has
been
shown,
mainly
by
Hershey
and
his
colleagues,
that
PROTEIN
SYNTHESIS
145
whereas
the
DNA
of
the
infecting
phage
penetrates
into
the
bacterial
cell
almost
all
the
protein
remains
outside
(see
the
review
by
Hershey,
1956);
and
also
on
Transforming
Factor,
which
appears
to
be
pure
DNA,
and
which
in
at
least
one
case,
that
of
the
enzyme
mannitol
phosphate
dehydro-
genase,
controls
the
synthesis
of
a
protein
(Marmur
&
Hotchkiss,
1955).
There
is
also
the
indirect
evidence
that
DNA
is
the
most
constant
part
of
the
genetic
material,
and
that
genes
control
proteins.
Finally
there
is
the
very
recent
evidence,
mainly
due
to
the
work
of
Benzer
on
the
rII
locus
of
bacteriophage,
that
the
functional
genethe
cistron
of
Benizers
termind-
logyconsists
of
many
sites
arranged
strictly
in
a
linear
order
(Benzer,
1957)
as
one
might
expect
if
a
gene
controls
the
order
of
the
amino
acids
in
some
particular
protein.
;
As
is
well
known,
the
correlation
between
ribonucleic
acid
(RNa)
and
protein
synthesis
was
originally
pointed
out
by
Brachet
and
by
Caspersson.
Is
there
any
more
direct
evidence
for
this
connexion?
In
particular
is
thete
anything
to
support
the
idea
that
the
sequentialization
of the
amino
acids
is
controlled
by
the
RNA?
foe
The
most
telling
evidence
is
the
recent
work
on
tobacco
mosaic
virus.
A
number
of
strains
of
the
virus
are
known,
and
it
is
not
difficult
to
show
(since
the
protein
sub-unit
of
the
virus
is
small)
that
they
differ
in
amino
acid
composition.
Some
strains,
for
example,
have
histidine
in
their
protein,
whereas
others
have
none.
Two
very
significant
experiments
have
been
carried
out.
In
one,
as
first
shown
by
Gierer
&
Schramm
(1956),
the
RNA
of
the
virus
alone,
although
completely
free
of
protein,
appears
to
be
infective,
though
the
infectivity
is
low.
In
the
other,
first
done
by
Fraenkel-
Conrat,
it
has
proved
possible
to
separate
the
RNA
from
the
protein
of
the
virus
and
then
recombine
them
to
produce
virus
again.
In
this
case
the
infectivity
is
comparatively
high,
though
some
of
it
is
usually
lost.
If
a
recombined
virus
is
made
using
the
RNA
of
one
strain
and
the
protein
of
another,
and
then
used
to
infect
the
plant,
the
new
virus
produced
in
the
plant
resembles
very
closely
the
strain
from
which
the
RNA
was
taken.
If
this
strain
had
a
protein
which
contained
no
histidine
then
the
offspring
will
have
no
histidine
either,
although
the
plant
had
never
been
in
contact
with
this
particular
protein
before
but
only
with
the
RNA
from
that
strain.
In
other
words
the
viral
RNA
appears
to
carry
at
least
part
of
the
informa-
tion
which
determines
the
composition
of
the
viral
protein,
Moreover
the
viral
protein
which
was
used
to
infect
the
cell
was
not
copied
to
any
appreciable
extent
(Fraenkel-Conrat,
1956).
It
has
so
far
not
proved
possible
to
carry
out
this
experimenta
model
of
its
kindin
any
other
system,
although
very
recently
it
has
been
claimed
that
for
two
animal
viruses
the
RNA
alone
appears
to
be
infective.
10
EBS
XII
146
PROTEIN
SYNTHESIS
Turnover
experiments
have
shown
that
while
the
labelling
of
DNA
is
homogeneous
that
of
RNA
is
not.
The
RNA
of
the
cell
is
partly
in
the
nucleus,
partly in
particles
in
the
cytoplasm
and
partly
as
the
soluble
RNA
of
the
cell
sap;
many
workers
have
shown
that
all
these
three
fractions
turn
over
differently.
It
is
very
important
to
realize
in
any
discussion
of
the
role
of
RNA
in
the
cell
that
it
is
very
inhomogeneous
metabolically,
and
probably
of
more
than
one
type.
The
site
of
protein
synthesis
There
is
no
known
case
in
Nature
in
which
protein
synthesis
proper
(as
opposed
to
protein
modification)
occurs
outside
cells,
though,
as
we
shall
see
later,
a
certain
amount
of
protein
can
probably
be
synthesized
using
broken
cells
and
cell
fragments.
The
first
question
to
ask,
therefore,
is
whether
protein
synthesis
can
take
place
in
the
nucleus,
in
the
cytoplasm,
or
in
both.
It
is
almost
certain
that
protein
synthesis
can
take
place
in
the
cytoplasm
without
the
presence
of the
nucleus,
and
it
is
probable
that
it
can
take
place
to
some
extent
in
the
nucleus
by
itself
(see
the
review
by
Brachet
&
Chantrenne,
1956).
Mirsky
and
his
colleagues
(see
the
review
by
Mirsky,
Osawa
&
Allfrey,
1956)
have
produced
evidence
that
some
protein
synthesis
can
occur
in
isolated
nuclei,
but
the
subject
is
technically
difficult
and
in
this
review
I
shall
quite
arbitrarily
restrict
myself
to
protein
synthesis
in
the
cytoplasm.
In
recent
years
our
knowledge
of
the
structure
of
the
cytoplasm
has
enormously
increased,
due
mainly
to
the
technique
of
cutting
thin
sections
for
the
electron
microscope.
The
cytoplasm
of
many
cells
contains
an
_
endoplasmic
reticulum
of
double
membranes,
consisting
mainly
of
protein
and
lipid
(see
the
review
of
Palade,
1956).
On
one
side
of
each
membrane
appear
small
electron-dense
particles
(Palade,
1955).
Bio-
chemical
studies
(Palade
&
Siekevitz,
1956;
among
others)
have
shown
that
these
particles,
which
are
about
100-200
A.
in
diameter,
consist
almost
entirely
of
protein
and
RNA,
in
about
equal
quantities.
Moreover
the
major
part of
the
RNA
of
the
cell
is
found
in
these
particles.
When
such
a
cell
is
broken
open
and
the
contents
fractionated
by
centrifugation,
the
particles,
together
with
fragments
of
the
endoplasmic
reticulum,
are
found
in
the
microsome
fraction,
and
for
this
reason
I
shall
refer
to
them
as
microsomal
particles.
These
microsomal
particles
are
found
in
almost
all
cells.
They
are
particularly
common
in
cells
which
are
actively
synthesizing
protein,
whereas
the
endoplasmic
reticulum
is
most
conspicuously
present
in
(mammalian)
cells
which
are
secreting
very
actively.
Thus
both
the
cells
PROTEIN
SYNTHESIS
147
of
the
pancreas
and
those
of
an
ascites
tumour
contain
large
quantities
of
microsomal
particles,
but
the
tumour
has
little
endoplasmic
reticulum,
whereas
the
pancreas
has
a
lot.
Moreover,
there
is
no
endoplasmic
reti-
culum
in
bacteria.
On
the
other
hand
particles
of
this
general
description
have
been
found
in
plant
cells
(Tso,
Bonner
&
Vinograd,
1956),
in
yeast,
and
in
various
bacteria
(Schachman,
Pardee
&
Stanier,
1953);
in
fact
in
all
cells
which
have
been
examined
for
them.
These
particles
have
been
isolated
from
various
cells
and
examined
inthe
.
ultra-centrifuge
(Petermann,
Mizen
&
Hamilton,
1952;
Schachmani
et
al.
1953;
among
others).
The
remarkable
fact
has
emerged
that
they
do
not
have
a
continuous
distribution
of
sedimentation
constants,
but
usitally
fall
into
several
well-defined
groups.
Moreover
some
of
the
particles
ate
prob-
ably
simple
aggregates
of
the
others
(Petermann
&
Hamilton,
t957).
This
uniformity
suggests
immediately
that
the
particles,
which
have
moleculat
weights
of
a
few
million,
have
a
definite
structure.
They
are;
in
fact,
reminiscent
of
the
small
spherical
RNA-containing
viruses,
and
Watson
©
and
I
have
suggested
that
they
may
have
a
similar
type
of
substructure
(Crick
&
Watson,
1956).
,
Biologists
should
contrast
the
older
concept
of
microsomes
with
the
more
recent
and
significant
one
of
microsomal
particles.
Microsomes
came
in
all
sizes,
and
were
irregular
in
composition;
microsomal
particles
occur
in
a
few
sizes
only,
have
a
more
fixed
composition
and
a
much
higher
pro-
portion
of
RNA.
It
was
hard
to
identify
microsomes
in
all
cells,
whereas
RNA-rich
particles
appear
to
occur
in
almost
every
kind
of
cell.
In
short,
microsomes
were
rather
a
mess,
whereas
microsomal
particles
appeal
immediately
to
ones
imagination.
It
will
be
surprising
if
they
do
not
prove
to
be
of
fundamental
importance.
It
should
be
noted,
however,
that
Simpson
and
his
colleagues
(Simpson
&
McLean,
1955;
Simpson,
McLean,
Cohn
&
Brandt,
1957)
have
reported
that
protein
synthesis
can
take
place
in
mitochondria.
It
is
known
that
,
mitochondria
contain
RNA,
and
it
would
be
of
great
interest
to
know
whether
this
RNA
is
in
some
kind
of
particle.
Mitochondria
are,
of
course,
very
widely
distributed
but
they
do
not
occur
in
lower
forms
such
as
bacteria.
Similar
remarks
about
RNA
apply
to
the
reported
incorporation
in
chloroplasts
(Stephenson,
Thimann
&
Zamecnik,
1956).
Microsomal
particles
and
protein
synthesis
It
has
been
shown
by
the
use
of
radioactive
amino
acids
that
during
protein
synthesis
the
amino
acids
appear
to
flow
through
the
microsomal
particles.
The
most
striking
experiments
are
those
of
Zamecnik
and
his
Io-2
148
PROTEIN
SYNTHESIS
co-workers
on
the
livers
of
growing
rats
(see
the
review
by
Zamecnik
et
al.
1956).
Two
variations
of the
experiment
were
made.
In
the
first
the
rat
was
given
a rather
large
intravenous
dose
of
a
radioactive
amino
acid.
After
a
predetermined
time
the
animal
was
sacrificed,
the
liver
extracted,
its
cells
homogenized
and
the
contents
fractionated.
It
was
found
that
the
micro-
somal
particle
fraction
was
very
rapidly
labelled
to a
constant
level.
In
the
second
a
very
small
shot
of
the
radioactive
amino
acid
was
given,
so
that
the
liver
received
only
a
pulse
of
labelled
amino
acid,
since
this
small
amount
was
quickly
used
up.
In
this
case
the
radioactivity
of
the
micro-
somal
particles
rose
very
quickly
and
then
fell
away.
Making
plausible
assumptions
Zamecnik
and
his
colleagues
have
shown
that
this
behaviour
is
what
one
would
expect
if
most
of
the
protein
of
the
microsomal
particles
was
metabolically
inert,
but
1
or
2%
was
turning
over
very
rapidly,
say
within
a
minute
or
so.
Very
similar
results
have
been
obtained
by
Rabinovitz
&
Olson
(1956,
1957)
using
intact
mammalian
cells,
in
this
case
rabbit
reticulocytes.
They
have
also
been
able to
show
that
the
label
passed
into a
well-defined
globular
protein,
namely
haemoglobin.
Experiments
along
the
same
general
lines
have
also
been
reported
for
liver
by
Simkin
&
Work
(19574).
We
thus
have
direct
experimental
evidence
that
the
microsomal
particles
are
associated
with
protein
synthesis,
though
the
precise
role
they
play
is
not
clear.
Activating
enzymes
It
now
seems
very
likely
that
the
first
step
in
protein
synthesis
is
the
activation
of
each
amino
acid
by
means
of
its
special
activating
enzyme.
The
activation
requires
ATP,
and
the
evidence
suggests
that
the
reaction
is
amino
acid
+
ATP
=
AMP
amino
acid +
pyrophosphate.
The
activated
amino
acid,
which
is
probably
a
mixed
anhydride
of
the
form
Oo
NH,
l
|
OPORiboseAdenine
RCC
|
|
og
0
H
in
which
the
carboxyl
group
of
the
amino
acid
is
phosphorylated,
appears
to
be
tightly
bound
to
its
enzyme
and
is
not
found
free
in
solution.
These
enzymes
were
first
discovered
in
the
cell-sap
fraction
of
rat
liver
cells
by
Hoagland
(Hoagland,
1955;
Hoagland,
Keller
&
Zamecnik,
1956)
and
in
yeast
by
Berg
(1956).
They
have
been
shown
by
DeMoss
&
Novelli
(1956)
to
be
widely
distributed
in bacteria,
and
it
is
surmised
that
they
occur
PROTEIN
SYNTHESIS
149
in
all
cells
engaged
in
protein
synthesis.
Recently
Cole,
Coote
&
Work
(1957)
have
reported
their
presence
in
a
variety
of
tissues
from
a
number
of
animals,
So
far
good
evidence
has
been
found
for
this
reaction
for
about
half
the
standard
twenty
amino
acids,
but
it
is
believed
that
further
research
will
reveal
the
full
set.
Meanwhile
Davie,
Koningsberger
&
Lipmann
(1956)
have
purified
the
tryptophan-activating
enzyme.
It
is
specific
for
trypto-
phan
(and
certain
tryptophan
analogues)
and
will
only
handle
the
L-isomer.
Isolation
of
the
tyrosine
enzyme
has
also
been
briefly
reported
(Konings-
berger,
van
de
Ven
&
Overbeck,
1957;
Schweet,
1957).
The
properties
of
these
enzymes
are
obviously
of
the
greatest
interest,
and
much
work
along
these
lines
may
be
expected
in
the
near
future,
For
example,
it
has
been
shown
that
the
tryptophan-activating
enzyme
contains
what
is
probably
a
derivative
of
guanine
(perhaps
GMP)
very
tightly
bound.
It
is
possible
to
remove
it,
however,
and
to
show
that
its
presetice
is
not
necessary
for
the
primary
activation
step.
Since
the
enzyme:
is
probably
involved
in
the
next
step
in
protein
synthesis
it
is
naturally
suspected
that
the
guanine
derivative
is
also
required
fot
this
reaction,
whatever
it
may
be.
Foote
PN
ade,
In
vitro
incorporation
os
In
order
to
study
the
relationship
between
the
activating
enzymes
and
the
microsomal
particles
it
has
proved
necessary
to
break
open
the
cells
and
work
with
certain
partly
purified
fractions.
Unfortunately
it
is
rare
to
obtain
substantial
net
protein
synthesis
from
such
systems,
and
there
is
a
very
real
danger
that
the
incorporation
of
the
radioactivity
does
not
represent
true
synthesis
but
is
some
kind
of
partial
synthesis
or
exchange
reaction.
This
distinction
has
been
clearly
brought
out
by
Gale
(1953).
The
work
to
be
described,
therefore,
has
to
be
accepted
with
reservations.
(See
the
remarks
of
Simkin
&
Work,
this
Symposium.)
It
has
been
shown,
however,
in
the
work
described
below,
that
the
amino
acid
is
incorporated
into
true
peptide
linkage.
Again
the
significant
results
were
first
obtained
by
Zamecnik
and
his
co-
workers
(reviewed
in
Zamecnik
et
al.
1956).
The
requirements
so
far
known
appear
to
fall
into
two
parts:
(1)
The
activation
of
the
amino
acids
for
which,
in
addition
to
the
labelled
amino
acid,
one
requires
the
pH
5
fraction,
containing
the
activating
enzymes,
ATP
and
(usually)
an
ATP-generating
system.
There
appears
to
be
no
requirement
for
any
of
the
pyrimidine
or
guanine
nucleotides.
(2)
The
transfer
to
the
microsomal
particles.
For
this
one
requires
the
previous
system
plus
GTP
or
GDP
(Keller
&
Zamecnik,
1956)
and
of
150
PROTEIN
SYNTHESIS
course
the
microsomal
particles;
the
endoplasmic
reticulum
does
not
appear
to
be
necessary
(Littlefield
&
Keller,
1957).
Hultin
&
Beskow
(1956)
have
reported
an
experiment
which
shows
clearly
that
the
amino
acids
become
bound
in
some
way.
They
first
incubate
the
mixture
described
in
(1)
above.
They
then
add
a
great
excess
of
unlabelled
amino
acid
before
adding
the
microsomal
particles.
Nevertheless
some
of
the
labelled
amino
acid
is
incorporated
into
protein,
showing
that
it
was
in
some
place
where
it
could
not
readily
be
diluted.
Very
recently
an
intermediate
reaction
has
been
suggested
by
the
work
of
Hoagland,
Zamecnik
&
Stephenson
(1957),
who
have
discovered
that
in
the
first
step
the
soluble
RNA
contained
in
the
pH
5
fraction
became
labelled
with
the
radioactive
amino
acid.
The
bond
between
the
amino
acid
and
the
RNA
appears
to
be
a
covalent
one.
This
labelled
RNA
can
be
extracted,
purified,
and
then
added
to
the
microsomal
fraction.
In
the
presence
of
GTP
the
labelled
amino
acid
is
transferred
from
the
soluble
RNA
to
microsomal
protein.
This
very
exciting
lead
is
being
actively
pursued.
Many
other
experiments
have
been
carried
out
on
cell-free
systems,
in
particular
by
Gale
&
Folkes
(1955)
and
by
Spiegelman
(see
his
review,
1957),
but
I
shall
not
describe
them
here
as
their
interpretation
is
difficult.
It
should
be
mentioned
that
Gale
(reviewed
in
Gale,
1956)
has
isolated
from
hydrolysates
of
commercial-yeast
RNA
a
series
of
fractions
which
greatly
increase
amino
acid
incorporation.
One
of
them,
the
so-called
glycine
incorporation
factor
has
been
purified
considerably,
and
an
attempt
is
being
made
to
discover
its
structure.
RNA
turnover
and
protein
synthesis
From
many
points of
view
it
seems
highly
likely
that
the
presence
of
RNA
is
essential
for
cytoplasmic
protein
synthesis,
or
at
least
for
specific
protein
synthesis.
It
is
by
no
means
clear,
however,
that
the
turnover
of
RNA
is
required.
In
discussing
this
a
strong
distinction
must
be
made
between
cells
which
are
growing,
and
therefore
producing
new
microsomal
particles,
and
cells
which
are
synthesizing
without
growth,
and
in
which
few
new
microsomal
particles
are
being
produced.
This
is
a
difficult
aspect
of
the
subject
as
the
evidence
is
to
some
extent
conflicting.
It
appears
reasonably
certain
that
not
all
the
RNA
in
the
cytoplasm
is
turning
over
very
rapidlythis
has
been
shown,
for
example,
by
the
Hokins
(1954)
working
on
amylase
synthesis
in
slices
of
pigeon
pancreas,
though
in
the
light
of
the
recent
work
of
Straub
(this
Symposium)
the choice
of
amylase
was
unfortunate.
On
the
other
hand
Pardee
(1954)
PROTEIN
SYNTHESIS
151
has
demonstrated
that
mutants
of
Escherichia
coli
which
require
uracil
or
adenine
cannot
synthesize
f-galactosidase
unless
the
missing
base
is
provided.
Can
RNA
be
synthesized
without
protein
being
synthesized?
This
can
be
brought
about
by
the
use
of
chloramphenicol.
In
bacterial
systems
chloramphenicol
stops
protein
synthesis
dead,
but
allows
RNA
synthesis
to
continue.
A
very
interesting
phenomenon
has
been
uncovered
in
E.
coli
by
Pardee
&
Prestidge
(1956),
and
by
Gros
&
Gros
(1956).
If
a
mutant
is
used
which
requires,
say,
leucine,
then
when
the
external
supply
of
leucine
is
exhausted
both
protein
and
RNA
synthesis
cease.
If
now
chloram-.
phenicol
is
added
there
is
no
effect,
but
if
in
addition
the
cells
are
given
a-
small
amount
of
leucine
then
rapid
RNA
synthesis
takes
place:
If
the
chloramphenicol
is
removed,
so
that
protein
synthesis
restarts,
then
this
leucine
is
built
into
proteins
and
then,
once
again,
the
synthesis
of
both
protein
and
RNA
is
prevented.
In
other
words
it
appears
as
if
free*
leucine
(i.e.
not
bound
into
proteins)
is
required
for
RNA
synthesis.
This
effect
is
not
peculiar
to
leucine
and
has
already
been
found
for
several
amino
acids
and
in
several
different
organisms
(Yéas
&
Brawerman,
1957):
As
a
number
of
people
have
pointed
out,
the
most
likely
interpretation
of
these
results
is
that
protein
and
RNA
require
common
intermediates
for
their
synthesis,
consisting
in
part
of
amino
acids
and
in
part
of
RNA
components
such
as
nucleotides.
This
is
a
most
valuable
idea;
it
explains
a
number
of
otherwise
puzzling
facts
and
there
is
some
hope
of
getting
close
to
it
experimentally.
For
completeness
it
should
be
stated
that
Anfinsen
and
his
co-workers
have
some
evidence
that
proteins
are not
produced
from
(activated)
amino
acids
in
a
single
step
(see
the
review
by
Steinberg,
Vaughan
&
Anfinsen,
1956),
since
they
find
unequal
labelling
between
the
same
amino
acid
at
different
points
on
the
polypeptide
chain,
but
this
interpretation
of
their
results
is
not
accepted
by
all
workers
in
the
field.
This
is
discussed
more
fully
by
Simkin
&
Work
(this
Symposium).
Summary
of
experimental
work
Both
DNA
and
RNA
have
been
shown
to
carry
some
of
the
specificity
for
protein
synthesis.
The
RNA
of
almost
all
types
of
cell
is
found
mainly
in
rather
uniform,
spherical,
virus-like
particles
in
the
cytoplasm,
known
as
microsomal
particles.
Most
of
their
protein
and
RNA
is
metabolically
rather
inert.
Amino
acids,
on
their
way
into
protein,
have
been
shown
to
pass
rapidly
through
these
particles.
An
enzyme
has
been
isolated
which,
when
supplied
with
tryptophan
and
ATP,
appears
to
form
an
activated
tryptophan.
There
is
evidence
that
1§2
PROTEIN
SYNTHESIS
there
exist
similar
enzymes
for
most
of
the
other
amino
acids.
These
enzymes
are
widely
distributed
in
Nature.
Work
on
cell
fractions
is
difficult
to
interpret
but
suggests
that
the
first
step
in
protein
synthesis
involves
these
enzymes,
and
that
the
subsequent
transfer
of
the
activated
amino
acids
to
the
microsomal
particles
requires
GTP.
The
soluble
RNA
also
appears
to
be
involved
in
this
process.
Whereas
the
presence
of
RNA
is
probably
required
for
true
protein
synthesis
its
rapid
turnover
does
not
appear
to
be
necessary,
at
least
not
for
all
the
RNA.
There
is
suggestive
evidence
that
common
intermediates,
containing
both
amino
acids
and
nucleotides,
occur
in
protein
synthesis.
IV.
IDEAS
ABOUT
PROTEIN
SYNTHESIS
It
is
an
extremely
difficult
matter
to
present
current
ideas
about
protein
synthesis
in
a
stimulating
form.
Many
of
the
general
ideas
on
the
subject
have
become
rather
stale,
and
an
extended
discussion
of
the
more
detailed
theories
is
not
suitable
in
a
paper
for
non-specialists.
1
shall
therefore
restrict
myself
to
an
outline
sketch
of
my
own
ideas
on
cytoplasmic
protein
synthesis,
some
of
which
have
not
been
published
before.
Finally
I
shall
deal
briefly
with
the
problem
of
coding.
General
principles
My
own
thinking
(and
that
of
many
of
my
colleagues)
is
based
on
two
general
principles,
which
I
shall
call
the
Sequence
Hypothesis
and
the
Central
Dogma.
The
direct
evidence
for
both
of
them
is
negligible,
but
I
have
found
them
to
be
of
great
help
in
getting
to
grips
with
these
very
complex
problems.
I
present
them
here
in
the
hope
that
others
can
make
similar
use
of
them.
Their
speculative
nature
is
emphasized
by
their
'
names.
It
is
an
instructive
exercise
to
attempt
to
build
a
useful
theory
without
using
them.
One
generally
ends
in
the
wilderness.
The
Sequence
Hypothesis
This
has
already
been
referred
to
a
number
of
times.
In
its
simplest
form
it
assumes
that
the
specificity
of
a
piece
of
nucleic
acid
is
expressed
solely
by
the
sequence
of
its
bases,
and
that
this
sequence
is
a
(simple)
code
for
the
amino
acid
sequence
of
a
particular
protein.
This
hypothesis
appears
to
be
rather
widely
held.
Its
virtue
is
that
it
unites
several
remarkable
pairs
of
generalizations:
the
central
biochemical
importance
of
proteins
and
the
dominating
biological
role
of
genes,
and
in
particular
of
their
nucleicacid;
the
linearity
of
protein
molecules
(considered
covalently)
and
the
genetic
linearity
within
the
functional
gene,
as
shown
by
the
work
of
Benzer
(1957)
and
Pontecorvo
(this
Symposium);
the
simplicity
PROTEIN
SYNTHESIS
153
of
the
composition
of
protein
molecules
and
the
simplicity
of
the
nucleic
acids.
Work
is
actively
proceeding
in
several
laboratories,
including
our
own,
in
an
attempt
to
provide
more
direct
evidence
for
this
hypothesis.
The
Central
Dogma
This
states
that
once
information
has
passed
into
protein
it
cannot
get
out
again.
In
more
detail,
the
transfer
of
information
from
nucleic
acid
to
nucleic
acid,
or
from
nucleic
acid
to
protein
may
be
possible,
but
transfer
from
protein
to
protein,
or
from
protein
to
nucleic
acid
is
im-
possible.
Information
means
here
the
precise
determination
of
sequence,
either
of
bases
in
the
nucleic
acid
or
of
amino
acid
residues in
the
protein.
This
is
by
no
means
universally
heldSir
Macfarlane
Burnet,
for
example,
does
not
subscribe
to
itbut
many
workers
now
think
along
these
lines.
As
far
as
I
know
it
has not
been
explicitly
stated
before.
Some
ideas
on
cytoplasmic
protein
synthesis
From
our
assumptions
it
follows
that
there
must
be an
RNA
template
in
the
cytoplasm.
The
obvious
place
to
locate
this
is
in
the
microsomal
particles,
because
their
uniformity
of
size
suggests
that
they
have
a
regular
structure.
It
also
follows
that
the
synthesis
of
at
least
some
of
the
micro-
somal
RNA
must
be
under
the
control
of
the
DNA
of the
nucleus.
This
is
because
the
amino
acid
sequence
of the
human
haemoglobins,
for
example,
is
controlled
at
least
in
part
by
a
Mendelian
gene,
and
because
spermatozoa
contain
no
RNA.
Therefore,
granted
our
hypotheses,
the
information
must
be
carried
by
DNA.
What
can
we
guess
about
the
structure
of
the
microsomal
particle?
On
our
assumptions
the
protein
component
of
the
particles
can
have
no
significant
role
in
determining
the
amino
acid
sequence
of
the
proteins
which
the
particles
are
producing.
We
therefore
assume
that
their
main
function
is
a
structural
one,
though
the
possibility
of
some
enzyme
activity
is
not
excluded.
The
simplest
model
then
becomes
one
in
which
each
particle
is
made
of
the
same
protein,
or
proteins,
as
every
other
one
in
the
cell,
and
has
the
same
basic
arrangement
of
the
RNA,
but
that
different
particles
have,
in
general,
different
base-sequences
in
their
RNA,
and
therefore
produce
different
proteins.
This
is
exactly
the
type
of
structure
found
in
tobacco
mosaic
virus,
where
the
interaction
between
RNA
and
protein
does
not
depend
upon
the
sequence
of bases
of
the
RNA
(Hart
&
Smith,
1956).
In
addition
Watson
and
I
have
suggested
(Crick
&
Watson,
1956),
by
analogy
with
the
spherical
viruses,
that
the
protein
of
microsomal
particles
is
probably
made
of
many
identical
sub-units
arranged
with
cubic
symmetry.
154
PROTEIN
SYNTHESIS
On
this
oversimplified
picture,
therefore,
the
microsomal
particles
in
a
cell
are
all
the
same
(except
for
the
base-sequence
of
their
RNA)
and
are
metabolically
rather
inert.
The
RNA
forms
the
template
and
the
protein
supports
and
protects
the
RNA.
This
idea
is
in
sharp
contrast
to
what
one
would
naturally
assume
at
first
glance,
namely
that
the
protein
of
the
microsomal
particles
consists
entirely
of
protein
being
synthesized.
The
surmise
that
most
of
the
protein
is
structural
was
derived
from
considerations
about
the
structure
of
virus
particles
and
about
coding;
it
was
independent
of
the
direct
experimental
evidence
of
Zamecnik
and
his
colleagues
that
only
a
small
fraction
of
the
protein
turns
over
rapidly,
so
that
this
agreement
between
theory
and
experiment
is
significant,
as
far
as
it
goes.
It
is
obviously
of
the
first
importance
to
know
how
the
RNA
of
the
particles
is
arranged.
It
is
a
natural
deduction
from
the
Sequence
Hypo-
thesis
that
the
RNA
backbone
will
follow
as
far
as
possible
a
spatially
regular
path,
in
this
case
a
helix,
essentially
because
the
fundamental
operation
of
making
the
peptide
link
is
always
the
same,
and
we
therefore
expect
any
template
to
be
spatially
regular.
Although
we
do
not
yet
know
the
structure
of
isolated
RNA
(which
may
be
an
artifact)
we
do
know
that
a
pair
of
RNA-like
molecules
can
under
some
circumstances
form
a double-helical
structure,
somewhat
similar
to
DNA,
because
Rich
&
Davies
(1956)
have
shown
that
when
the
two
polyribotides,
polyadenylic
acid
and
polyuridylic
acid
(which
have
the
same
backbone
as
RNA)
are
mixed
together
they
wind
round
one
another
to
form
a
double
helix,
presumably
with
their
bases
paired.
It
would
not
be
surprising,
therefore,
if
the
RNA
backbone
took
up
a
helical
configura-
tion
similar
to
that
found
for
DNA.
This
suggestion
is
in
contrast
to
the
idea
that
the
RNA
and
protein
interact
in
a
complicated,
irregular
way
to
form
a
nucleoprotein.
As
far
as
I
know
there
is
at
the
moment
no
direct
experimental
evidence
to
decide
between
these
two
points
of
view.
However,
even
if
it
turns
out
that
the
RNA
is
(mainly)
helical
and
that
the
structural
protein
is
made
of
sub-units
arranged
with
cubic
symmetry
it
is
not
at
all
obvious
how
the
two
could
fit
together.
In
abstract
terms
the
problem
is
how
to
arrange
a
long
fibrous
object
inside
a
regular
poly-
hedron.
It
is
for
this
reason
that
the
structure
of
the
spherical
viruses
is
of
great
interest
in
this
context,
since
we
suspect
that
the
same
situation
occurs
there;
moreover
they
are
at
the
moment
more
amenable
to
experimental
attack.
A
possible
arrangement,
for
example,
is
one
in
which
the
axes of
the
RNA
helices
run
radially
and
clustered
in groups
of
five,
though
it
is
always
possible
that
the
arrangement
of the
RNA
is
irregular.
PROTEIN
SYNTHESIS
155
It
would
at
least
be
of
some
help
if
the
approximate
location
of
the
RNA
in
the
microsomal
particles
could
be
discovered.
Is
it
on
the
outside
or
the
inside
of
the
particles,
for
example,
or
even
both?
Is
the
microsomal
particle
a
rather
open
structure,
like
a
sponge,
and
if
it
is
what
size
of
molecule
can
diffuse
in
and
out
of
it?
Some
of
these
points
are
now
ripe
for
a
direct
experimental
attack.
The
adaptor
hypothesis
Granted
that
the
RNA
of the
microsomal
particles,
regularly
arranged,
is
the
template,
how
does
it
direct
the
amino
acids
into
the
correct
order?
Ones
first
naive
idea
is
that
the
RNA
will
take
up.a
configuration
capable
of
forming
twenty
different
cavities,
one
for
the
side-chain
of
each
of
the
.
twenty
amino
acids.
If
this
were
so
one
might
expect
to
be
able to
play
the
problem
backwardsthat
is,
to
find
the
configuration
of
RNA
by
trying
to
form
such
cavities,
All
attempts
to
do
this
have
failed,
and
on
physical-
chemical
grounds
the
idea
does
not
seem
in
the
least
plausible
(Crick,
1957a).
Apart
from
the
phosphate-sugar
backbone,
which
we
have
assumed
to
be
regular
and
perhaps
linked
to
the
structural
protein
of
the
particles,
RNA
presents
mainly
a
sequence
of
sites
where
hydrogen
bonding
could
occur.
One
would
expect,
therefore,
that
whatever
went
on
to
the
tem-
plate
in
a
specific
way
did
so
by
forming
hydrogen
bonds.
It
is
therefore
a
natural
hypothesis
that
the
amino
acid
is
carried
to
the
template
by
an
adaptor
molecule,
and
that
the
adaptor
is
the
part
which
actually
fits
on
to
the
RNA.
In
its
simplest
form
one
would
require
twenty
adaptors,
one
for
each
amino
acid.
What
sort
of
molecules
such
adaptors
might
be
is
anybodys
guess.
They
might,
for
example,
be
proteins,
as
suggested
by
Dounce
(1952)
and
by
the
Hokins
(1954)
though
personally
I
think
that
proteins,
being
rather
large
molecules,
would
take
up
too
much
space.
They
might
be
quite
unsuspected
molecules,
such
as
amino
sugars.
But
there
is
one
possibility
which
seems
inherently
more
likely
than
any
otherthat
they
might
contain
nucleotides.
This
would
enable
them
to join
on
to
the
RNA
template
by
the
same
pairing
of
bases
as
is
found
in
DNA,
or
in
polynucleotides.
If
the
adaptors
were
small
molecules
one
would
imagine
that
a
separate
enzyme
would
be
required
to
join
each
adaptor
to
its
own
amino
acid
and
that
the
specificity
required
to
distinguish
between,
say,
leucine,
iso-
leucine
and
valine
would
be
provided
by
these
enzyme
molecules
instead
of
by
cavities
in
the
RNA.
Enzymes,
being
made
of
protein,
can
probably
make
such
distinctions
more
easily
than
can
nucleic
acid.
An
outline
picture of
the
early
stages
of
protein
synthesis
might
be
as
156
PROTEIN
SYNTHESIS
follows:
the
template
would
consist
of
perhaps
a
single
chain
of
RNA.
(As
far
as
we
know
a
single
isolated
RNA
backbone
has
no
regular
con-
figuration
(Crick,
19575)
and
one
has
to
assume
that
the
backbone
is
supported
in
a
helix
of
the
usual
type
by
the
structural
protein
of
the
microsomal
particles.)
Alternatively
the
template
might
consist
of
a
pair
of
chains.
Each
adaptor
molecule
containing,
say,
a
di-
or
trinucleotide
would
each
be
joined
to
its
own
amino
acid
by
a
special
enzyme.
These
molecules
would
then
diffuse
to
the
microsomal
particles
and
attach
to
the
proper
place
on
the
bases
of
the
RNA
by
base-pairing,
so
that
they
would
then
be
in
a
position
for
polymerization
to
take
place.
It
will
be
seen
that
we
have
arrived
at
the
idea
of
common
intermediates
without
using
the
direct
experimental
evidence
in
their
favour;
but
there
is
one
important
qualification,
namely
that
the
nucleotide
part
of
the
inter-
mediates
must
be
specific
for
each
amino
acid,
at
least
to
some
extent.
It
is
not
sufficient,
from
this
point
of
view,
merely
to
join
adenylic
acid
to
each
of
the
twenty
amino
acids.
Thus
one
is
led
to
suppose
that
after
the
acti-
vating
step,
discovered
by
Hoagland
and
described
earlier,
some
other
more
specific
step
is
needed
before
the
amino
acid
can
reach
the
template.
The
soluble
RNA
If
trinucleotides,
say,
do
in
fact
play
the
role
suggested
here
their
synthesis
presents
a
puzzle,
since
one
would
not
wish
to
invoke
too
many
enzymes
to
do
the
job.
It
seems
to
me
plausible,
therefore,
that
the
twenty
different
adaptors
may
be
synthesized
by
the
breakdown
of
RNA,
probably
the
soluble
RNA.
Whether
this
is
in
fact
the
same
action
which
the
activating
enzymes
carry
out
(presumably
using
GTP
in
the
process)
remains
to
be
seen.
From
this
point
of
view
the
RNA
with
amino
acids
attached
reported
recently
by
Hoagland,
Zamecnik
&
Stephenson
(1957),
would
be
a
half-
way
step
in
this
process
of
breaking
the
RNA
down
to
trinucleotides
and
joining
on
the
amino
acids.
Of
course
alternative
interpretations
are
possible.
For
example,
one
might
surmise
that
numerous
amino
acids
become
attached
to
this
RNA
and
then
proceed
to
polymerize,
perhaps
inside
the
microsomal
particles.
I
do
not
like
these
ideas,
because
the
supernatant
RNA
appears
to
be
too
short
to
code
for
a
complete
poly-
peptide
chain,
and
yet
too
long
to
join
on
to
template
RNA
(in
the
micro-
somal
particles)
by
base-pairing,
since
it
would
take
too
great
a
time
for
a
piece
of
RNA
twenty-five
nucleotides
long,
say,
to
diffuse
to
the
correct
place
in
the
correct
particles.
If
it
were
only
a
trinucleotide
on
the
other
hand,
there
would
be
many
different
correct
places
for
it
to
go
to
(where-
ever
a
valine
was
required,
say),
and
there
would
be
no
undue
delay.
PROTEIN
SYNTHESIS
157
Leaving
theories
on
one
side,
it
is
obviously
of
the
greatest
interest
to
know
what
molecules
actually
pass
from
the
pH
5
enzymes
to
the
microsomal
particles,
Are
they
small
molecules,
free
in
solution,
or
are
they
bound
to
protein?
Can
they
be
isolated?
This
seems
at
the
moment
to
be
one
of
the
most
fruitful
points
at
which
to
attack
the
problem,
i
et
Subsequent
steps
What
happens
after
the
common
intermediates
have
entered
the
microsomal
particles
is
quite
obscure.
Two
views
are
possible,
which
might
be
called
the
Parallel
Path
and
the
Alternative
Path
theories.
In
the.
first
an
intermediate
is
used
to
produce
both
protein
and
RNA
at
about
the
_
same
time.
In
the
second
it
is
used
to
produce
either
protein,
or
RNA,
but
not
both.
If
we
knew
the
exact
nature
of
the
intermediates
we
could
prob-
ably
decide
which
of
the
two
was
more
likely..
At
the
moment
there
seems
_
little
reason
to
prefer
one
theory
to
the
other..
tae
Ae
gh?
The
details
of
the
polymerization
step
are
also
quite
unkstowii,,|
One
.
tentative
theory,
of the
Parallel
Path
type,
suggests
that
the
intetinediates
first
polymerize
to give
an
RNA
molecule
with
amino
acids
attached.
This
process
removes
it
from
the
template
and
it
diffuses
outside
the
microsomal
particle.
There
the
RNA
folds
to
a
new
configuration,
and
the
amino
acids
become
polymerized
to
form
a
polypeptide
chain,
which
folds
up
as
it
is
made
to
produce
the
finished
protein.
The
RNA,
now
free
of
amino
acids,
is
then
broken
down
to
produce
fresh
intermediates,
A
great
variety
of
theories
along
these
lines
can
be
constructed.
I
shall
not
discuss
these
further
here,
nor
shall
I
describe
the
various
speculations
about
the
actual
details
of
the
chemical
steps involved.
Two
types
of
RNA
It
is
an
essential
feature
of
these
ideas
that
there
should
be
at
least
two
types
of
RNA
in
the
cytoplasm.
The
first,
which
we
may
call
template
RNA
is
located
inside
the
microsomal
particles.
It
is
probably
synthesized
in
the
nucleus
(Goldstein
&
Plaut,
1955)
under
the
direction
of
DNA,
and
carries
the
information
for
sequentialization.
It
is
metabolically
inert
during
protein
synthesis,
though
naturally
it
may
show
turnover
whenever
micro-
somal
particles
are
being
synthesized
(as
in
growing
cells),
or
breaking
down
(as
in
certain
starved
cells).
The
other
postulated
type
of
RNA,
which
we
may
call
metabolic
RNA,
is
probably
synthesized
(from
common
intermediates)
in
the
microsomal
par-
ticles,
where
its
sequence
is
determined
by
base-pairing
with
the
template
RNA.
Once
outside
the
microsomal
particles
it
becomes
soluble
RNA
and
is
constantly
being
broken
down
to
form
the
common
intermediates
158
PROTEIN
SYNTHESIS
with
the
amino
acids.
It
is
also
possible
that
some
of
the
soluble
RNA
may
be
synthesized
in
a
random
manner
in
the
cytoplasm;
perhaps,
in
bacteria,
by
the
enzyme
system
of
Grunberg-Manago
&
Ochoa
(1955).
One
might
expect
that
there
would
also
be
metabolic
RNA
in
the
nucleus.
The
existence
of
these
different
kinds
of
RNA
may
well
explain
the
rather
conflicting
data
on
RNA
turnover.
The
coding
problem
So
much
for
biochemical
ideas.
Can
anything
about
protein
synthesis
be
discovered
by
more
abstract
arguments?
If,
as
we
have
assumed,
the
sequence
of
bases
along
the
nucleic
acid
determines
the
sequence
of
amino
acids
of
the
protein
being
synthesized,
it
is
not
unreasonable
to
suppose
that
this
inter-relationship
is
a
simple
one,
and
to
invent
abstract
descrip-
tions
of
it.
This
problem
of
how,
in
outline,
the
sequence
of
four
bases
codes
the
sequence
of
the
twenty
amino
acids
is
known
as
the
coding
problem.
It
is
regarded
as
being
independent
of
the
biochemical
steps
involved,
and
deals
only
with
the
transfer
of information.
This
aspect
of
protein
synthesis
appeals
mainly
to
those
with
a
background
in
the
more
sophisticated
sciences.
Most
biochemists,
in
spite
of
being
rather
fascinated
by
the
problem,
dislike
arguments
of
this
kind.
It
seems
to
them
unfair
to
construct
theories
without
adequate
experimental
facts.
Cosmologists,
on
the
other
hand,
appear
to
lack
such
inhibitions.
The
first
scheme
of
this
kind
was
put
forward
by
Gamow
(1954).
It
was
supposedly
based
on
some
features
of
the
structure
of
DNA,
but
these
are
irrelevant.
The
essential
features
of
Gamows
scheme
were
as
follows:
(a)
Three
bases
coded
one
amino
acid.
(5)
Adjacent
triplets
of
bases
overlapped.
See
Fig.
1.
(c)
More
than
one
triplet
of
bases
stood
for
a
particular
amino
acid
(degeneracy).
In
other
words
it
was
an
overlapping
degenerate
triplet
code.
Such
a
code
imposes
severe
restrictions
on
the
amino
acid
sequences
it
can
produce.
It
is
quite
easy
to
disprove
Gamows
code
from
a
study
of
known
sequences
even
the
sequences
of
the
insulin
molecule
are
sufficient.
However,
there
are
a
very
large
number
of
codes
of
this
general
type.
It
might
be
thought
almost
impossible
to
disprove
them
all
without
enumerating
them,
but
this
has
recently
been
done
by
Brenner
(1957),
using
a
neat
argument.
He
has
shown
that
the
reliable
amino
acid
sequences
already
known
are
enough
to
make
all
codes
of
this
type
impossible.
Attempts
have
been
made
to
discover
whether
there
are
any
obvious
restrictions
on
the
allowed
amino
acid
sequences,
although
the
sequence
data
available
are
very
meagre
(see
the
review
by
Gamow,
Rich
&
Yéas,
PROTEIN
SYNTHESIS
159
1955).
So
far
none
has
been
found,
and
the
present
feeling
is
that
it
may
well
be
that
none
exists,
and
that
any
sequence
whatsoever
can
be
produced.
This
is
very
far
from
being
established,
however,
and
for
all
we
know
there
may
be
quite
severe
restrictions
on
the
neighbours
of
the
rarer
amino
acids,
such
as
tryptophan.
If
there
is
indeed
a
relatively
simple
code,
then
one
of
the
most
important
biological
constants
is
what
Watson
and
I
have
called
the
coding
ratio
(Crick
&
Watson,
1956).
If
B
consecutive
bases.are
requited
to
code
A
consecutive
amino
acids,
the
coding
ratio
is
the
number
B/A;
when
B
and
A
are
large.
Thus
in
Gamows
code
its
value
is
unity;
since
a
stting
of
1000
bases,
for
example,
could
code
998
amino
acids.
(Notice
that
when
the
coding
ratio
is
greater
than
unity
stereochemical
problems.
arise,
.
since a
polypeptide
chaiii
has
4 distance of
only
about
3}
A:
between
its
residues,
which
is
about
the
minimum
distance
between
sitccessive
bases
in
nucleic
acid.
However,
it
has
been
pointed
out
by
Brenner
(personal
communication),
that
this
difficulty
may
not
be
serious
if
the
polypeptide
chain
leaves
the
template
as
it
is
being
synthesized.)
B.C
ACODODABABODC
BCA
Overlapping
code
|
c
7 D
Cc
DD
Pode,
Partial
overlapping
code
DDA
\
ABA
f
BCA
CDD
Non-overlapping
code
ABA
\
BDC
Fig.
1.
The
letters
A,
B,
C,
and
D
stand
for
the
four
bases
of
the
four
common
nucleotides,
The
top
row
of
letters
represents
an
imaginary
sequence
of
them.
In
the
codes
illustrated
here
each
set
of
three
letters
represents
an
amino
acid.
The
diagram
shows
how
the
first
four
amino
acids
of
a
sequence
are
coded
in
the
three
classes
of
codes.
If
the
code
were
of
the
non-overlapping
type
(see
Fig.
1)
one
would
still
require
a
triplet
of
bases
to
code
for
each
amino
acid,
since
pairs
of
bases
would
only
allow
4 x
4=16
permutations,
though
a
possible
but
not
very
likely
way
round
this
has
been
suggested
by
Dounce,
Morrison
&
Monty
(1955).
The
use
of
triplets
raises
two
difficulties.
First,
why
are
there
not
4%
4%x4=64
different
amino
acids?
Second,
how
does
one
know
which
of
the
triplets
to
read
(assuming
that
one
doesnt
start
at
an
end)?
For
example,
if
the
sequence
of
bases
is
....
ABA,
CDB,
BCA,
ACC,
...,
where
A,
B,
C
and
D
represent
the
four
bases,
and
where
ABA
is
supposed
to
code
one
amino
acid,
CDB
another
one,
and
so
on,
how
could
one
read
it
correctly
if
the
commas
were removed?
160
PROTEIN
SYNTHESIS
Very
recently
Griffith,
Orgel
and
I
have
suggested
an
answer
to
both
these
difficulties
which
is
of
some
interest
because
it
predicts
that
there
should
be
only
twenty
kinds
of
amino
acid
in
protein
(Crick,
Griffith
&
Orgel,
1957).
Gamow
&
Yéas
(1955)
had
previously
put
forward
a
code
with
this
property,
known
as
the
combination
code
but
the
physical
assumptions
underlying
their
code
lack
plausibility.
We
assumed
that
some
of
the
triplets
(like
ABA
in
the
example
above)
correspond
to
an
amino
acidmake
sense
as
we
would
sayand
some
(such
as
BAC
and
ACD,
etc.,
above)
do
not
so
correspond,
or
as
we
would
say,
make
nonsense.
We
asked
ourselves
how
many
amino
acids
we
could
code
if
we
allowed
all
possible
sequences
of
amino
acids,
and
yet
never
accidentally
got
sense
when
reading
the
wrong
triplets,
that
is
those
which
included
the
imaginary
commas.
We
proved
that
the
upper
limit
is
twenty,
and
moreover
we
could
write
down
several
codes
which
did
in
fact
code
twenty
things.
One
such
code
of
twenty
triplets,
written
compactly
is
ABd
4¢
é
i
D
Sows
where
A
Ba
means
that
two
of
the
allowed
triplets
are
ABA
and
ABB,
etc.
The
example
given
a
little
further
back
has
been
constructed
using
this
code.
You
will
see
that
ABA,
CDB,
BCA
and ACC
are
among
the
allowed
triplets,
whereas
the
false
overlapping
ones
in
that
example,
such
as
BAC,
ACD
and
DBB,
etc.,
are
not.
The
reader
can
easily
satisfy
himself
that
no
sequence
of
these
allowed
triplets
will
ever
give
one
of
the
allowed
triplets
in.a
false
position.
There
are
many
possible
mechanisms
of
protein
synthesis
for
which
this
would
be an
advantage.
One
of
them
is
described
in
our
paper
(Crick
et
al.
1957).
Thus
we
have
deduced
the
magic
number,
twenty,
in
an
entirely
natural
way
from
the
magic
number
four.
Nevertheless,
I
must
confess
that
I
find
it
impossible
to
form
any
considered
judgment
of
this
idea.
It
may
be
complete
nonsense, or
it
may
be
the
heart
of
the
matter.
Only
time
will
show.
V.
CONCLUSIONS
I
hope
I
have
been
able
to
persuade
you
that
protein
synthesis
is
a
central
problem
for
the
whole
of
biology,
and
that
it
is
in
all
probability
closely
related
to
gene
action.
What
are
ones
overall
impressions
of
the
present
state
of
the
subject?
T'wo
things
strike
me
particularly.
First,
the
existence
of
general
ideas
covering
wide
aspects
of
the
problem.
It
is
remarkable
that
one
can
formulate
principles
such
as
the
Sequence
Hypothesis
and
the
PROTBIN
SYNTHESIS
161
Central
Dogma,
which
explain
many
striking
facts
and
yet
for
which
proof
is
completely
lacking.
This
gap
between
theory
and
experiment
is
4
gteat
stimulus
to
the
imagination.
Second,
the
extremely
active
state
of
the
subject
experimentally
both
on
the
genetical
side
and
the
biochemical
side.
At
the
moment
new
and
significant
results
are
being
reported
every
few
months,
and
there
seems
to
be
no
sign
of
work
coming
to
a
standstill
because
experimental
techniques
are
inadequate.
For
both
these
reasons
I
shall
be
surprised
if
the
main
features
of
protein
synthesis
dte
not
discovered
within
the
next
ten
years.
_
It
is
a
pleasure
to
thank
Dr
Sydney
Brenner,
not
only
for
many
.
interesting
discussions,
but
also
for
much
help
in
rédrafting
this
paper.
|
'
REFERENCES.
BEADLE,
-
7
(48).
Chem,
Rev.
37,
t5.
BNZER,
Y.
(1957).
In
The
Chemical
Basis
of
Heredity.'
Ed.
McElroy;
W!D,
é&
Glass,
B.
Baltimore:
Johns
Hopkins
Press.
'
AP
1,
Vi
Bano,
P,
(1956)
¥.
Biol.
Chem.
222,
1025.
Ce
ee
Hae
A
ORSOOK,
H.
(1956).
Proceedings
of
the
Third
International
Congress
of
Biocheniis
Brussels,
1955
(C.
Liébecq,
editor).
New
York:
Academic
Pre
po
os
Brace,
J.
&
Cuanrrenne,
H.
(1956).
Cold
Spr.
Harb.
Symp.
Quant.
Biol.
21,
9.
.
>
.
po,
!
wis
Brenner,
S.
(1957).
Proc.
Nat.
Acad.
Sct.,
Wash.
43,
687:
,
Brown,
N.
H.,
Sancer,
F.
&
Krrar,
R.
(1955).
Biochem.
F.
60,
556.
Cousn,
G.
N.
&
Cowir,
D.
B.
(1957).
C.R.
Acad.
Sci.,
Paris,
244,
680.
Coreg,
R.
D.,
Coore,
J.
&
Work,
T.
S.
(1957).
Nature,
Lond.
179,
199.
Crick,
F.
H.
Cc,
(19574).
In
The
Structure
of
Nucleic
Acids
and
Their.
Role
in
S
Protein
|
Synthesis,
Pp.
25.
Cambridge
University
Press.
RICK,
F.
H.
C,
(19575).
In
Cellular
Biology,
Nucleic
Acids
and
Vi
New
York
Academy
of
Sciences.
°
ey
T98T7-
Crick,
F.
H.
C.,
Grirritn,
J.
S.
&
Orex,
L.
E.
(1957).
Proc.
Nat.
Acad.
Sci.
Wash.
43,
416.
Crick,
F.
H.
C.
&
Watson,
J.
D.
(1956).
Ciba
Foundation
S
i
Nature
of
Viruses.
London:
Churchill.
m
Symposium
on
The
Daviz,
E.
W.,
Konincsnercer,
V.
V.
&
Lipmann,
F.
(1956).
Arch.
Biochem.
Biophys.
65,
21.
DrMoss,
J.
A.
&
Novetu,
G.
D.
(1956).
Biochim.
Biophys.
Acta,
22
Douncz,
A.
L.
(1952).
Enzymologia,
15,
251.
ri
49"
Dounce,
A.
L.
(1956).
¥.
Cell.
Comp.
Physiol.
47,
suppl.
1,
103.
Douncz,
A.
L.,
Morrison,
M.
&
Monty,
K.
J.
(1955).
Nature,
Lond:
176,
597.
FRAENKEL-Conrat,
H.
(1956).
¥.
Amer.
Chem.
Soc.
78,
882.
Gat,
E.
F.
(1953).
Advanc.
Protein
Chem.
8,
283.
Gates,
E.
F.
(1956).
Proceedings
of
the
Third
International
Congress
of
Biochemistry,
Brussels,
1955
(C.
Liébecq,
editor).
New
York:
Academic
Press.
Gate,
E.
F,
&
Fouxes,
J.
(1955).
Biochem.
F.
59,
661,
675
and
730.
Gamow,
(1954).
Nature,
Lond.
173,
318.
amow,
G.,
Rich,
A.
&
Yéas,
M.
(1955).
Advanc.
Biol.
Med.
York:
Academic
Press.
soe
ot
Bios
4
New
II
162
PROTEIN
SYNTHESIS
Gamow,
G.
&
Yéas,
M.
(1955).
Proc.
Nat.
Acad.
Sci.,
Wash.
41,
1101.
Grrner,
A.
&
Scuramm,
G.
(1956).
Z.
Naturf.
116,
138;
also
Nature,
Lond.
177,
702.
Goxpstein,
L.
&
Praut,
W.
(1955).
Proc.
Nat.
Acad.
Sci.,
Wash.
41,
874.
Gros,
F.
&
Gros,
F.
(1956).
Biochim.
Biophys.
Acta,
22,
200.
Grunperc-Manaco,
M.
&
Ocuoa,
S.
(1955).
¥.
Amer.
Chem.
Soc.
77,
3165.
Harris,
J.
I.,
SaNcgr,
F,
&
Naucuton,
M.
A.
(1956).
Arch.
Biochem.
Biophys.
65,
427.
Hart,
R.
G.
&
Situ,
J.
D.
(1956).
Nature,
Lond.
178,
739-
Hersuey,
A.
D.
(1956).
Advances
in
Virus
Research.
1V.
New
York:
Academic
Press.
HoacLanp,
M.
B.
(1955).
Biochim.
Biophys.
Acta,
16,
288.
Hoactanp,
M.
B.,
Kecuer,
E.
B.
&
ZAMECNIK,
P.
C.
(1956).
JF.
Biol.
Chem.
218,
345-
Hoac.anp,
M.
B.,
Zamecnix,
P.
C.
&
STEPHENSON,
M.
L.
(1957).
Btochim.
Biophys.
Acta,
24,
215.
Hoxrn,
L.
E.
&
Hoxin,
M.
R.
(1954).
Biochim.
Biophys.
Acta,
13,
401.
Huxtin,
T.
&
Beskow,
G.
(1956).
Exp.
Cell
Res.
11,
664.
IncraM,
V.
M.
(1956).
Nature,
Lond.
178,
792.
:
Incram,
V.
M.
(1957).
Nature,
Lond.
180,
326.
Kamin,
H.
&
Hanpuer,
P.
(1957).
Annu.
Rev.
Biochem.
26,
419.
Kewier,
E.
B.
&
ZaMECNIK,
P.
C.
(1956).
.
Biol.
Chem.
221,
45.
KonINGSBERGER,
V.
V.,
VAN
DE
VEN,
A.
M.
&
Overneck,
J.
Tu.
G.
(1957).
Proc.
K.
Akad.
Wet.
Amst.
B,
60,
141.
Larrierrmp,
J.
W.
&
Kevrer,
E.
B.
(1957).
f.
Biol.
Chem.
224,
13:
-
Marmovr,
J.
&
Horcuniss,
R.
D.
(1955).
F.
Biol.
Chem.
214,
383.
Mirsky,
A.
E.,
Osawa,
S.
&
ALLFREY,
V.
G.
(1956).
Cold
Spr.
Harb.
Symp.
Quant.
Biol.
21,
49.
_Munter,
R.
&
Coungn,
G.
N.
(1956).
Biochim.
Biophys.
Acta,
21,
592.
Patapg,
G.
E.
(1955).
J.
Biochem.
Biophys.
Cytol.
1,
1.
,Pazang,
G.
E.
(1956).
J.
Biochem.
Biophys.
Cytol.
2,
85.
Pauapg,
G.
E.
&
Smxevitz,
P.
(1956).
F.
Biochem.
Biophys.
Cytol.
2,
171.
Parpge,
A.
B.
(1954).
Proc.
Nat.
Acad.
Sci.,
Wash.
40,
263.
Parner,
A.
B.
&
Prestipee,
L.
8.
(1956).
¥.
Bact.
71,
677.
PauLine,
L.,
Irano,
H.
A.,
Srncer,
S.
J.
&
Wes,
I.
C.
(1949).
Science,
110,
543-
PETERMANN,
M.
L.
&
Hamiton,
M.
G.
(1957).
J.
Biol.
Chem.
224,
7253
also
Fed.
Proc.
16,
232.
PETERMANN,
M.
L.,
Mizen,
N.
A.
&
HAMILTON,
M.
G.
(1952).
Cancer
Res.
12,
373.
Rapinovitz,
M.
&
Orson,
M.
E.
(1956).
Exp.
Cell
Res.
10,
747.
Rasinovitz,
M.
&
Otson,
M.
E.
(1957).
Fed.
Proc.
16,
235.
Ricn,
A.
&.
Davies,
D.
R.
(1956).
F.
Amer.
Chem.
Soc.
78,
3548.
ScHacuMan,
H.
K.,
Parpgg,
A.
B.
&
STANIER,
R.
Y.
(1953).
Arch.
Biochem.
Biophys.
43,
381-
Scuwest,
R.
(1957).
Fed.
Proc.
16,
244.
Simin,
J.
L.
&
Work,
T.
8.
(19572).
Biochem.
F.
65,
307.
Simin,
J.
L.
&
Worx,
T.
S.
(19578).
Nature,
Lond.
179,
1214.
Srmrson,
M.
V.
&
McLean,
J.
R.
(1955).
Biochim.
Biophys.
Acta,
18,
573.
Simpson,
M.
V.,
McLzan,
J.
R.,
CoH,
G.
I.
&
Branot,
I.
K.
(1957).
Fed.
Proc.
16,
249.
SPIEGELMAN,
S.
(1957).
In
The
Chemical
Basis
of
Heredity.
Ed.
McElroy,
W.
D.
&
Glass,
B.
Baltimore:
Johns
Hopkins
Press.
Sretnperc,
D.
&
Mimacyt,
E.
(1957).
In
Annu.
Rev.
Biochem.
26,
373.
Sremperc,
D.,
VaucHan,
M.
&
ANFINSEN,
C.
B.
(1956).
Science,
124,
389.
PROTEIN
SYNTHESIS
163
StTepuenson,
M.
L.,
T
Biophes,
6s,
ty.
HIMANN,
K.
V.
&
ZAMECNIK,
P.
C.
(1956).
Arch.
Biochem
Synog,
R.
(1957).
In
The
Origin
of
Life
on
the
Earth.
U.S.S.R.
Acad.
of
Sciences.
Tso,
P.
O.
B.,
B
Y
ee
Bonner,
J.
&
Vinocrap,
J.
(1956).
7.
Biochem.
Biophys.
Cytol.
2,
Wacner,
R.
P.
&
Mitcuert,
H.
K.
i ;
Toba
Wiley
amd
Soe
(1955).
Genetics
and
Metabolism.
New
York:
Yéas,
M.
&
Brawerman,
G.
(1
i
i
.
»
G.
(1957).
Arch.
Biochem.
Biophys.
68
ZAMECNIK,
F.
C.,
Ketier,
E.
B.,
Lirrtert.p,
J.
W.,
Heactanp
a
&
Lort-
FIELD,
R.
B.
(1956).
J.
Cell.
Comp.
Physiol.
47,
suppl.
1,81.
> "My own thinking (and that of many of my colleagues) is based on two general principles, which I shall call the Sequence Hypothesis and the Central Dogma. The direct evidence for both of them is negligible, but I have found them to be of great help in getting to grips with these very complex problems. I present them here in the hope that others can make similar use of them. Their speculative nature is emphasized by their names. It is an instructive exercise to attempt to build a useful theory without using them. One generally ends in the wilderness"
James Watson and Francis Crick worked together (along with Rosalind Franklin) when they discovered the helical structure of DNA (in the 1950s). DNA itself was discovered in the 1860s by Swiss chemist Friedrich Miescher.
> "Biologists should not deceive themselves with the thought that some new class of biological molecules, of comparable importance to the proteins, remains to be discovered. This seems highly unlikely. In the protein molecule Nature has devised a unique instrument in which an underlying simplicity is used to express great subtlety and versatility; it is impossible to see molecular biology in proper perspective until this peculiar combination of virtues has been clearly grasped."
Francis Harry Compton Crick (June 1916 – July 2004) was an English molecular biologist who played a crucial role in discovering the helical structure of DNA.
> "This family likeness between the same protein molecules from different species is the rule rather than the exception."
> "By contrast the most significant thing about proteins is that they can do almost anything. In animals proteins are used for structural purposes, but this is not their main role, and indeed in plants this job is usually done by polysaccharides. The main function of proteins is to act as enzymes, Almost all chemical reactions in living systems are catalysed by enzymes, and all known enzymes are protein."
Some more background on amino acids: https://en.wikipedia.org/wiki/Amino_acid