A molecular geneticist reflects on two general historical questions;
(1) What does
it mean to say a discovery is
Ciahead of its time”?
(2) Are scientific creations any less unique than artistic creations?
\
i
by Gunther S. Stent
u-
:
T
he fantastically rapid progress of
molecular genetics in the past 25
years now obliges merely middle-
aged participants in
its early develop-
ment to look back on their early work
from a depth of historical perspective
that for scientific specialties flowering in
earlier times came only after all the wit-
nesses of the first blossoming were long
dead.
It
is as
if the late-18th-ceritury
colleagues of Joseph Priestley and An-
toine Lavoisier had
still been active in
chemical research and teaching in the
1930’s,
after atomic structure and the
nature of the chemical bond had been
revealed.
This
somewhat
depressing
personal vantage provides a singular op-
portunity
to
assay
the
evolution
of a
scientific
field. In reflecting on the his-
tory
of
molecular
genetics
from
the
viewpoint of my own experience I have
found that two of
its most famous inci-
dents—Oswald Avery’s identification of
DNA as the active principle in bacterial
transformation and hence as genetic ma-
terial, and James Watson and
Francis
Crick’s discovery of the DNA double he-
lix—illuminate two general problems of
cultural
history.
The
case
of
Avery
throws light on the question of whether
it
is meaningful or merely tautologous
to say that a discovery
is “ahead of
its
time,”
or premature. And
the case
of
Watson and Crick can be used, and in
fact has been used, to discuss the ques-
tion. of whether there is anything unique
in a scientific discovery, in view of the
likelihood that
if Dr. A had not discov-
ered
I
1 act A
today, Dr. B would have
discovered it tomorrow.
pice years ago I published a brief ret-'
respective
essay
on
molecular
ae-
netics, with paAp&f
fjfe
I
f'
origins. In that historical account I men-
tioned neither Avery’s name nor DNA-
mediated bacterial transformation. My
essay elicited a letter to the editor by a
microbiologist, who complained:
"It
is
a sad and
surprising omission
that...
Stent makes no mention of the definitive
proof of DNA as the basic hereditary
substance by O. T. Avery, C. M. Mac-
Leod and Maclyn McCarty, The growth
of [molecular genetics] rests upon this
experimental proof. ... I am old enough
to remember
the
excitement and
en-
thusiasm induced by the publication of
the paper by Avery, MacLeod and Mc-
Carty. Avery, an effective bacteriologist,
was a quiet, self-effacing, non-disputa-
tious gentleman. These characteristics of
personality should not [cause] the gen-
eral scientific public... to let his name
go unrecognized."
I was taken aback by this letter and
replied that I should indeed have men-
tioned Avery’s 1944 proof that DNA is
the hereditary substance.
1 went on to
say, however, that
in my opinion
it
is
not true that the growth of molecular
genetics
rests
on
Avery’s
proof.
For
many years that proof actually had little
impact on geneticists. The reason for the
delay was not that Avery’s work was un-
known
to or mistrusted by
geneticists
but that it was “premature.”
My
pritna
facie
reason
for
saying
Avery’s discovery was premature is that
it was not appreciated
in
its day. by
lack of appreciation
I do not mean that
Avery’s
discovery went
unnoticed,
or
even that
it was not considered impor-
tant. What I do mean is that geneticists
did not seem
to be able
to do much
with
it or build on it. That is, in
its day
.Av££y’xdi?CttVMX tod v.irt«jil’
mrse'ot
This statement can be
readily sup-
ported by an examination of the scien-
tific literature. For example, a convinc-
ing demonstration of the lack of appre-
ciation of Avery’s discovery is provided
by theT950 golden jubilee of genetics
symposium “Genetics in the 20th Cen-
tury."
Itr the proceedings of that sym-
posium some of the most eminent ge-
neticists published essays that surveyed
the progress of the first 50 years of ge-
netics and
assessed
its
status
at
that
time. Only one of the 26 essayists saw
fit to make more than a passing refer-
ence to Avery’s discovery, then six years
old. He was a colleague of Avery’s at
the
Rockefeller
Institute,
and he
ex-
pressed
some
doubt
that
the
active
transforming principle was really pure
DNA. The then leading philosopher of
the gene, H.
J. Muller of Indiana Uni-
versity, contributed an essay on the na-
ture of the gene that mentions neither
Avery nor DNA.
So why was Avery’s discovery not ap-
preciated
in
its
day? Because
it was
premature.” But
is
this
really an
ex-
planation or
is
it nrerely air empty tau-
tology? In other words,
is there a way
of providing a criterion of the prema-
turity of a discovery other than its fail-
ure
to make an impact? Yes, there
is
such a criterion: A discovery
is prema-
ture
if
its implications cannot be con-
nected by a series of simple logical steps
to
canonical,
or
generally
accepted,
knowledge.
Why could Avery’s discovery not be
connected
with
canonical
knowledge?
Ever since DNA had been discovered in
the cell nucleus by Friedrich Miesclrer
in 1869
it had been suspected of exert-
—
.
__ v0G&4uS Pr-
esses. Tins
suspicion became stronger
I
.
. ?
.rjsi
.
.iP.
V-
t
'•
»
in the 1920’s, when
it was found that
even when it was finally realized by the
DNA is a major component of the chro-_iarly,1940Y thaL die moVcu]erL weight
niosomApp«QMftctdfi®ri Rataaai^fl40
molecular
nature
of DNA,
however,
the tetrnnucleotide hvodthesis remii.M
made
it
well-nigh
inconceivable
that
DNA could be the earner of hereditary
information.
First,
until
well
into
the
1930’s DNA was generally thought
to
lie merely a tetranucleotide composed
o.f one unit each of adenylic, guanylic,
thymidylic and cytidylic acids. Second,
the tetrnnucleotide hypothesis required,
it was
still widely believed the tetranu-
cleotide was the basic repeating unit of
the large DNA polymer in which the
four
units mentioned recur
in
regular
sequence. DNA was
therefore viewed
as a uniform macroniolecule
that,
like
other
monotonous
polymers
such
as
stain'll or cellulose,
is always the same,
r
S0U1 tc-
riTe ubiquitous presence of DNA in the
chromosomes was
therefore
generally
explained
in
purely
physiological
or
stiuctuml
terms.
It was usually to the
chromosomal protein that the informa-
tional
role of the genes had been
as-
signed,
since
the
great
differences
in
the specificity of structure that exist be-
tween various proteins in the same or-
•
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.f DEMOISELLES D’AVICNON,” painted in Par-
na n«i„!
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C,t
by art historian9 as
fi™major Cubist
’* ?* ,“"d
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“ m,le6,,,ne "> die development of modern art. It is
artistic ere ^ ** an arc,,ejype of the proposition that works of
Approved ^or‘1^effeSiS^5£IOltoS726x'
jfesaSSMt
isted, it would never have been painted), whereas works of e.ien-
tific creation are inevitable (in the sense that
if Dr. A had not dis-
covered Fact X today,' Dr. B would discover it tomorrow). The va-
lidity of the proposition
is disputed by the author. The painting
CIAiR&P^^M7CTfmQO2(K)0&OO64^ New York.
I
mole*
point
ciated since the beginning of the cen-
sociated with the name of Gregor Men-
of
view,
however,
was
irreconcilable
*
tury. The
conceptual
difficulty
of
as-
del, whose discovery of the gene in 1865
with Polanyi’s basic assumption of the
signing the genetic role to DNA had not
had to wait 35 years before it was “redis-
mutual independence of individual gas
escaped Avery. In the conclusion of his
covered”
at
the
turn
of
the
century,
molecules in the adsorption process. It
paper he stated:
“If the
results of the
Mendel’s discovery made no immediate
was only in the 1930’s, after a new the-
'
present study of the transforming prin-
impact,
it can be argued, because the
ory of cohesive molecular forces based
ciple are confirmed, then nucleic acids
concept
of
discrete
hereditary
units
on quantum-mechanical resonance rath-
must be regarded as possessing biologi-
could not be connected with canonical
er than on electrostatic attraction had
cal
specificity
the
chemical
basis
of
knowledge of anatomy and physiology
been
developed,
that
it became
con-
'
which is as yet undetermined.”
in the middle of the 19th century. Fur-
ceivable gas molecules could behave in
By
1950, however, the
tetranucleo-
thermore,
the
statistical
methodology
the way Polanyi’s experiments indicated
tide hypothesis had been overthrown,
by means of which Mendel interpreted
they were actually behaving. Meanwhile
>
thanks
largely
to
the work
of Erwin
the results of his pea-breeding experi-
Polanyi’s theory had been consigned so
Chargaff
of
the
Columbia
University
ments was entirely foreign to the way
authoritatively to the ashcan of crackpot
College of Physicians and Surgeons. He
of thinking of contemporary biologists,
ideas that it was rediscovered only in the
showed that, contrary to the demands
By the end of the 19th century, how-
1950’s.
I
of that hypothesis, the four nucleotides
ever,
chromosomes
and
the
chromo-
are not necessarily present in DNA in
some-dividing processes of mitosis and
Gtill, can the notion of prematurity be
equal
proportions. He found,
further-
meiosis had been discovered and Men-
^ said to be a useful historical concept?
more, that the exact nucleotide compo-
del’s results could now be accounted for
First of all, is prematurity the only pos-
sition of DNA differs according to
its
in terms of structures visible in the mi-
sible explanation
for the lack
of con-
.
biological source, suggesting that DNA
croscope. Moreover, by then the appli-
temporary appreciation of a discovery?
might
not be
a monotonous
polymer
cation of statistics
to biology had be-
Evidently not. For example, my micro-
S
after
all. And so when two years later,
come
commonplace.
Nonetheless,
in
biologist critic suggested that it was the
%
in
1952, Alfred Hershey and Martha
some
respects
Avery’s
discovery
is
a
“quiet,
self-effacing,
lion-disputatious”
J
Chase of the Carnegie Institution’s lab-
more dramatic example of prematurity
personality of Avery that was the cause
J
oratory
in Cold Spring Harbor,
N.Y.,
than Mendel’s. Whereas Mendel’s
dis-
of the failure of his contribution to be
showed that on infection of the host bac-
covery seems hardly to have been men-
recognized.
Furthermore,
in
an
essay
terium by a bacterial vims at least 80
tioned by anyone until
its rediscovery,
on the history of DNA research Chargaff
percent of the viral DNA enters the cell
Avery’s discovery was widely discussed
supports the idea that personal modesty
.
and at least 80 percent of the viral pro-
and yet it could not be appreciated for
arrd aversion
to self-advertisement
ac-
;
tein remains outside,
it was possible to
eight years.
count for the lack of contemporary sci-
'
connect
their conclusion
that DNA
is
Cases
of delayed
appreciation
of a
eutific
appreciation. He
attributes
the
the
genetic
material
with
canonical
discovery exist also in the physical sci-
75-year lag between Miescher’s discov-
'
knowledge.
Avery’s
“as
yet
undeter-
ences. One example (as well as
air ex-
ery of DNA and
lire general apprecia-
•
mined chemical basis of the biological
planation of its circumstances in terms
tion of its importance to Miescher’s be-
:.i
specificity of nucleic acids” could now
of the concept to which I refer here as
ing “one of the quiet in the land,” who
be seen as the precise sequence of the
prematurity)
has
been
provided
by
lived when
"the
giant
publicity ma-
'
four nucleotides along the polynucleo-
Michael Polanyi on the basis of his own
chines, which
today accompany even
j
tide chain. The general impact of the
experience.
In
the
years
1914-71916
the smallest move on the chess-board of
i
Hershey-Chase experiment was imme-
Polanyi published a theory of the ad-
nature with enormous fanfares, were not
»
gairisnr, or«t
different on
JHti
mos«£
HiiStiffl
m>7
diate and dramatic. DNA was suddenly
in and protein was out, as far as think-
ing about the nature of the gene was
concerned. Within a few months there
arose the first speculations about the ge-
netic code, and Watson and Crick were
inspired to set out to discover the struc-
ture of DNA.
Of course, Avery’s discovery
is only
one
of many premature discoveries
in
the history of science. I have presented
it here for consideration mainly because
of my own failure to appreciate it when
I joined Max Delbruek’s bacterial virus
group
at
the
California
Institute
of
Technology in 1948. Since then
I have
often wondered what my
later career
would have been like if I had only been
astute enough to appreciate Avery’s dis-
cover)- and infer from
it four years be-
sorption
of
gases on
solids which
as-
sumed
that
the force attracting a
gas
molecule to a solid surface depends only
on the position of the molecule, and not
on the presence of other molecules,
in
the force field. In spite of the fact that
Polanyi was able to provide strong ex-
perimental evidence in favor of his the-
ory,
it was generally rejected. Not only
was the theoiy rejected, it was also con-
sidered so ridiculous by the leading au-
thorities
of
the
time
that
Polanyi
be-
lieves continued defense of
his theoiy
would have ended his professional ca-
reer
if he had not managed
to publish
work on more palatable ideas. The rea-
son for the general rejection of Polanyi’s
adsorption theoiy was that at the very
time he put
it forward the role of elec-
trical forces in the architecture of matter
had just been discovered. Hence there
yet in place.” Indeed, the 35-year hiatus
POLYSACCHARIDE
CAPSULE
PNEUMOCOCCI’!
BACTERIA
fore Ilershey and Chase that DNA must
had just been discovered. Hence there
j,y
ti,e aul |,0r as a classic example
<
also be ^Aipp^q^e^ipof-(f^e4Qas&e2Q&1\ff)^/2€^p<^lA^RC)P9&uQ0787iR00&2QQ0S0QS4-5he
experimental organism.
tion of gases must also involve an elec-
normal, or S-type, pneumococcus, a
S STRAIN
EXPERIMENT OF 1944 with which Oswald
Avery correctly identified the chemical na-
ture
of
the
genetic
material
is
regarded
l»y the author as a classic example ol a pre*
S7lROOd-2dQO£0(154'5fie
virulent
normal, or S-lype, pneumococcus, a bacteri-
i
in the appreciation of Mendel's discov-
ery is Often
ing been a
mocrest monk
living in an
out-of-the-way
Moravian
monastery.
Hence the notion of prematurity pro-
vides an alternative to the invocation-
in my opinion an inappropriate one for
the
instances
mentioned
here—of
the
lack of publicity as an explanation for
delayed appreciation.
More important, does the prematurity
concept
pertain
only
to
retrospective
judgments made with
the wisdom
of
hindsight? No, I drink it can be used also
to judge the present, Some recent dis-
coveries are still premature at this veiy
time. One example of here-and-now pre-
maturity is the alleged finding that ex-
periential
information
received by an
animal can be stored in nucleic acids or
other macromolecules.
Some 10 years ago there began to ap-
pear reports by experimental psycholo-
gists purporting to have shown that the
engrain,
or memory
trace,
of
a
task
learned by a
trained
animal
can be
transferred to a naive animal by inject-
ing or feeding the recipient with an ex-
tract made from the tissues of the donor.
At that time the central lesson of mo-
lecular genetics—that nucleic acids and
proteins
are
informational macromole-
cules—had just gained wide currency,
and the facile equation of nervous in-
formation with genetic information soon
led
to
the
proposal
that
macromole-
cules-DNA,
RNA
or
_ protein—store
memory. As it happens, the experiments
on which the macromolecular theory of
memory is based have been difficult to
repeat, and the results claimed for them
may indeed not be true at all. It is none-
theless 'significant that few neurophysi-
ologists have even bothered
to check
these
experiments,
even
though
it
is
or
cnemical
memory
transfer
would
constitute a fact of capital importance.
The lack
of interest of neurophysiolo-
gists
in
the macromolecular theory of
memory can be accounted for by recog-
nizing that the theory, whether true or
false,
is clearly premature. There
is no
chain of reasonable inferences by means
of which our present, albeit highly im-
perfect, view of the functional organiza-
tion of the brain can be reconciled with
the possibility of
its acquiring, storing
and retrieving nervous information by
encoding such information in molecules
of nucleic acid or protein. Accordingly
for the community of neurophysiologists
there
is no point
in devoting time to
checking on experiments whose results,
even if they were true as alleged, could
not be connected with canonical knowl-
edge.
The concept of here-and-now prema-
turity can be applied also to the trouble-
some subject
of ESP,
or extrasensory
perception. In the summer of 1948
I
happened to hear a heated argument at
Cold Spring Harbor between two future
mandarins of molecular biology, Salva-
dor
Luria
of Indiana
University and
R. E. Roberts of the Carnegie Institu-
tion's laboratory in Washington. Roberts
was then interested in ESP, and he felt
it had not been given fair consideration
by the
scientific community. As
I
re-
call, he thought that one might be able
to
set up experiments with molecular
beams that could provide more defini-
tive
data on
the
possibility
of mind-
induced departures from random
dis-
tributions than J. B. Rhine’s then much
discussed
card-guessing
procedures.
Luria declared that not only was he not
interested
;n Roberts’ proposed experi-
OOT^kQfl02Od®aOi5i?4j5was un-
wortny or anyone claiming to be a scien-
tist even to discuss such rubbish. How
could an intelligent fellow such as Rob-
erts entertain the possibility of phenom-
ena totally irreconcilable with the most
elementary physical laws? Moreover, a
phenomenon
that
is
manifest only
to
specially endowed subjects, as claimed
by “parapsychologists"
to be
the case
for ESP,
is outside the proper realm of
science, which must deal with phenom-
ena accessible to every observer. Rob-
erts replied that far from him being un-
scientific,
it was Luria whose bigoted
attitude toward the unknown was un-
worthy of a true scientist. The fact that
not everyone has ESP only means that
it
is an elusive phenomenon, similar to
musical genius. And just because a phe-
nomenon
cannot
be
reconciled
with
what we now know, we need not shut
our eyes to it. On the contrary, it is the
duty of the scientist to try to devise ex-
periments designed
to probe
its truth
or falsity.
It seemed to me then that both Luria
and Roberts were right, and in the in-
tervening years
I often thought about
this puzzling disagreement, unable
to
resolve
it in my own mind. Finally six
years ago I read a review of a book on
ESP by my Berkeley colleague C. West
Churchipan, and I began to see my way
toward a resolution. Churchman stated
that there
are three
different possible
scientific approaches to ESP. The first of
these is that the truth or falsity of ESP,
like the truth or falsity of the existence
of God or of the immortality of the soul,
is
totally
independent
of
either
the
methods or the findings of empirical sci-
ence; Thus the problem of ESP
is de-
um that causes pneumonia
in mammals, is enclosed in a smooth
(hence S) polysaccharide capsule that protects the bacterium from
the ordinary defense mechanisms of the infected animal. The avir-
ulent mutant, or ii-type
(li for rough), strain has lost the genetic
capacity to form this protective capsule and hence is comparatively
harmless. WhenAfJpftifTOlB FtiH«iR€iea«e‘l20@1'/0$*26
S donor bacteria was added to mutant R recipient bacteria, some
of the mutants were found to regain the genetic capacity to form
the capsule and thus were transformed back into the normal, vir-
ulent S type. Avery purified the transforming principle and suc-
ceeded in showing that
it is DMA. The significance of Avery’s diB-
?<0tA*RE>P96p0O7'87R&§i&2©O080@S4*®tii 1952 .
is second approach
is
to
no other set of hypotheses in psychology
»
^
110
was
Churchman's second approach
is
to
reformulate
the ESP phenomenon
in
terms of currently acceptable scientific
notions, such as unconscious perception
or conscious fraud. Hence, rather than
defining ESP out of existence, it is triv-
ialized. The second approach probably
would have been acceptable
to Luria
too, but not to Roberts.
The
third approach
is
to take
the
proposition of ESP literally and to
at-
tempt to examine in all seriousness the
evidence for its validity. That was more
or less Roberts’ position. As Churchman
points out, however, this approach is not
likely
to
lead
to
satisfactory
results.
Parapsychologists
can
maintain
with
GUANINE
has received the degree of critical scru-
tiny that has been given to ESP experi-
ments. Moreover, many other phenom-
ena have been accepted on much less
statistical evidence than what is offered
for ESP. The
reason Churchman
ad-
vances for the futility of a strictly evi-
dential approach to ESP is that in the
absence of a hypothesis
of how ESP
could work it is not possible to decide
whether any set of relevant observations
can be accounted for only by ESP to the
exclusion of alternative explanations.
After reading Churchman’s review I
realized that Roberts would have been
ill-advised to proceed with his ESP ex-
CYTOSINE
as Luria
h;
-
not be “sciene
but because any positive evidence
]
might have found in favor of ESP wou
have been, and would
still be, prem
ture. That is,{until it is possible to ccr
nect ESP with canonical knowledge
c
say, electromagnetic radiation and ne;
ropbysiology no
demonstration
of
occurrence could be appreciated.
Is the lack of appreciation of prem
'
ture discoveries merely attributable
t
the
intellectual shortcoming or
innai
conservatism of scientists who, if the
,RESI
were
only more
perceptive
or
mot
;uIe aa
open-minded,
would
give
immedial
.anged
recognition to any well-documented sc nine i
entifjc proposition? Folanyi is not of the tine
is
opinion^ Reflecting on the cruel fate
c
his theory half a century after first ac
vancing
it, £e declared]) "This miscajbeen
riage of the scientific method could nc cassa
have been avoided. . . .Jjhere rnust be a scient
ctT all times a predominantly accepted sd claim
entific view of the nature of things, i very
the
light of which
research
is
joint! that
conducted by members of the commu make
nity of scientists. A strong presumplioi or C
<
that any
evidence
which
contradict
Or
this view is invalid must prevail. Sucl
self
i
evidence has to be disregarded, even i of
lit
it cannot be accounted for, in the hop
I
that
it will eventually turn out to
lx cmin
false or irrelevant.”
*
(the
That is a view of the operation of sci Man
ence rather different from the one com by &
monly held, under which acceptance
of man
authority
is
seen
as something to
be
evol
avoided at all costs. The good scientist
I time
is seen as an unprejudiced man with ani
„
open mind who is ready to embrace any
lutic
new idea supported by the facts. The
to n
history of science shows, however, that
trad
its
practitioners do not appear to
act
v>e'
according to that popular viewT?
|
THYMINE
ADENINE
JhtmlwT
t'
emlCa
i
1 Btr"CtUre of DNA *
until well into the 1930’s, saw
nvlirtwVl
f
tClr£macIeotiJ e composed of one unit each of adenylic, gua-
3 DNA £ IS
Cyl
;
y
" acids - This h>P° thesis demanded that the molecular weight
thySand moslT
•
,00°
th3t ,hC
f°Ur nUCle°tide b39- <*•»* Kuanine,
in lTl lVlO's
,]
° 1 °T “
eqnal proportions. Even when it was finally realised
ions)
it wasS M
^
° f °NA
*S mucb hi®her
(in
*he
«r
bll-
iZI n^r
dd/
bel,eved thBt ,he tetranucleotide was the ba
to he an
'FCH^R
©i
ftOflIQZJ2&nioC«*rtV
to he an obJTaHe to the eventual acceptance of the idea that DNA is the genetiTmaterial
TTive years ago Chargaff wrote one of
x
the many reviews
of The
Double
Helix,
Watson’s
autobiographical
ac-
count of his and Crick’s discovery of the
structure of DNA. In his review Char-
gaff observes that scientific autobiogra-
phy is
a most awkward literary genre."
Most such works, he says, "give the im-
pression of having been written for the
remainder tables of bookstores, reaching
them almost before they are published."
The reasons for this, according to Char-
gaff, are not far to seek: scientists “lead
monotonous and uneventful lives and...'
besides often do not know how to write."
Moreover,
there may also be profound-
er reasons for the general
triteness
of
—
.
•
-
-
_.
,
.
Ttmon
o/
-
-
oeen
written*
Xes Desmoiselles d’Avignon’ not have*
!I beS
lea;
eha
tan
the
sai
ha’