S_ C
S7 `13KIN(~ AND HEALT-H
An appreciation of the present
pcsition of research.
7
1. PRODUCTION OF A 'SAFER' CIGARETTE !ILL ...
Since we last reviewed this subject there has been
a
steady development in our ideas and one result is
that
it is possible to describe a strategy of research
which
could be valuable a9 a basis for co-ordinating our
joint
efforts.
/I There are various methods of making a cigarette
whose
condensate shows a smaller mouse skin effect than
that
from normal flue cured tobacco. These will be
discussed
in detail under other items of the Agenda, but two
issues
remain outstanding, whether such cigarettes would
be
sufficiently attr-active to establish a market in
their
own right, and further whether their claim to
acceptance
could be fortified' by claims of greater safety.
That such
cigarettes would be more attractive than those
currently
on the market is rather unlikely and therefore to
sell them
we should need so=e incentive. On present thinking
it
would be impossible for the manufacturers to use
the incentive
of.making health claims, the arguments against
this are well
known and this seems to leave an impasse.
A possible way out has been under discussion in
recent weeks.
This originated from a suggestion put forward by
Sir John
Richardson and Sir Charles Dodds. It is that the
T.R.C.
should set up and finance an entirely independent
committee,
on which it would not itself be represented, whose
sole
function would be to kee-o under review current
animal bio-assay
tests and to state their ouinion of their
relevaace to the
human situation. T.R.C. would invite some eminent
scientist
r\J
%01
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1. to be chairman but that is all they would do.
This
chairman would have a completely free hand to
choose
and to ask those who he wished to join him. The
freedom
from any influence by the tobacco industry would
be beyond
question and while Govern--ent and Medical
Authorities might
not be willing to go as fa-r as to endorse the
findings of
the committee they could not help being aware of
them. Thus
the manufacturers, while making no health claims,
could say
that their products had been tested by the
bio-assay methods
considered relevant or valuable by the Committee.
Further=ore,
a great deal of the work at Harrogate and a fair
amount of
that ca-rried out by'the co--panies would now have
a much more
immediate objective, that of producing evidence
which could
be put before this committee. There would be two
broad lines
of advance. First to show that our test methods
did in -fact
show up differences between cigarettes, since
instinctively
we assume that all smoking materials cannot be
identical in
their physiological effects and it would be a poor
test that
did not bring this to light. The next line would
be to endeavour
to understand what actua.1 processes were
happening in the
empirical tests since any advance in our knowledge
could be
of immediate advantage in lending credibility to
the test as
a valid index.
2. BRIDGING THE C%A-P
While the setting up of this independent committee
would
give relevance to much of the Harrogate work and
the work
privately financed by the Companies, there would
still remain
the central problem of relating animal experiments
to human
experience.
Both Sir John Richardson and Sir Charles Dodds
considered
that it was unlikely that it would ever be
possible to bridge
the gap in a meaningful sense. Probably in their
miads was
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2. the realisation zhat we cannot even at :,resent
predict
from experiments on mice the effects of a material
applied
to say a rat. Bat their argument; rests almost
entirely on
excessive relia:-ce on the catch phrase ..
"bridging the gap"
which now seems to have outlived its usefulness.
The basic
concept still provides a valid objective of
research and
what we are really thin-king of in this context is
of parallel
exDloration of the metabolic pathways of
chemically caused
carcinogenesis in animals and in man. T---is may
be difficult
to do but no one can assert that it is not a
feasible objective.
3. METABOLIC PATHW.AZS OF CHEI-ICAL
CARCINOG--,-LSIS
IN ANIMALS
Harrogate has started to work on the proli'ect of
tracing
how inh:aled materials can arrive at the basal
cells of an
animal. The working hypothesis is that w:ien smoke
aerosol
is taken into the lungs some of it "dissolves" in
the mucous
blanket. The vapour phase is in the molecular form
and there
may well be something approaching a
physio-chemical equilibrium
between the concentration in the air-space and the
concentration
of the separate materials in the mucus. The
droplets of.the
particulate phase on the other hand will almost
certainly tend
to lose their identity once they are taken up in
the mucus and
their content of chemical substance will be held
as separate
materials spread throughout the mucus.
The investigation of this first stage in -.he
pathway is
straightforward although difficult. It i=volves
extracting
mucus from the lungs of animals that have been
made to inhale
smoke and then investigating what chemical
materials are
present in the mucus and in what state. 7-, due
course, when
techniques have been fully established, it does
not seem
imnossible to ex-lzact mucus from human s=kers and
investigate
its content of smcke materials.
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1.
3. :-~-e present posi7-4on is that Harrogate is
lea-rr-4-::6 aboat
the chemistrj of zucus and. the techniques of
handling it.
!-, would be convenient for them in the early
staSes to get
=-zsus of smoking animals, such as pigs and sheep,
from
H-.Lntingdon Research Station and they hope to
esta7olis-'- that
t-'-e material does not change significantly in
the period
required for transit.
While it would'be logical to wait to know what
materials
are present in the mucus before endeavouring to
find out
how they can get to the basa.1 cells this is not
possible
in view of the urgency of the problem. T.R.C. has
therefore
commissioned Huntingdon Research Centre to
investigate the
hypothesis that the.pathway is via the cilia which
are of
course actively moving in the mucus. The
hypothesis
envi7sages that some of the chemical content of
the mucus
gets into the cytoplasm of the ciliated cell and
spreads
th.roughout the cell. At its lowest extremity the
ciliated
cell is in contac-. with basal cells and transDort
of material
across the two touching cell membranes could lead
to the entry
of material i-nto the basal cell.
H-R.C. have undertaken a three months study to
verify some
p.-eliminary experiments which showed that low
levels of
S=Oke could cause ultra- structural changes in the
cilia of
e--ithelial cells suggesting that they might be
acting as
c*annels to the inside of the cell. They also
propose to
ca--ry out autoradiography studies using labelled
benzp-,~rene
suspended in mam=alian mucus and to trace the
penetration
of the benzpyrene into the epithelial cells. If
this is
successful a three years study will be
commissioned.
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4. =AEOLIC FATHWk' DT MT OF C=C;LLY
CAUSED LUNG CANC~:R
Desoite the virulence of the attack by the medical
profession
on smoking there is little inte-rest on their part
into the
mechanism of how the inhalation of smoke could
cause the
disease. They seem satisfied with the
epider-iological
results that there is an association between the
number of
cigarettes smoked and the nu::ber of cases of lung
cancer.
It is certain that if the Industry is ever going
to know how
the disease is caused then they will themselves
have to
stimulate and to some extent direct the work since
even if
they make ample money available it wouid still be
almost
useless just to exhort medical research centres to
work on
the Droblem. The only feasible method is to think
up some
imvestigations, plan them out ourselves and then
pay some
trained medical research man to carry them out. We
=-,st face
the situation quite frankly t'--at as amateurs we
may not propose
very clever investigations but once we start and
have hired
staff we can rely on them to point this out and
the project
r v'11 be improved- The crux is simply that unless
we make a
JA
start nothing will ever happen.
A study of the literature sugi;ests the following
five lines
as possible starters for such researches.
(a) The state of coverage of the lung by cilia
disclosed at auto-isy of accident cases.
(b) The investigation of macrophages from healthy
smokers to find out if they contain significa7at
amounts of smoke material.
(c) The exact locatiom of lung cancers as
disclosed
at autopsy.
(d) The s=oking habits of people suspected of
having
lung cancer.
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4. (e) T--e relevance of recent a~'-7ances in
molecular
m -
biology to chemically cauza,-~ carcinogenesis.
(A) There is considerable con:roversy whether the
i-)la-lation of smoke lead5 -.;o permanent damage
to the cilia. If there are large bare patches
on the lung surface of a c:n-firmed smoker then,
as
Kotin has pointed out, the-se could provide a
direct
path of contact for the ='--e aerosol with the
basal
cells. If, 'on the otl7er h-=d, repair of the
cilia
continues until late in life then the pathway to
the
basal cells is possibly sc=.etl-,'ng more li-ke
what
has been suggested, that iS solution in the mucus
and transport through the ciliated and
intermediate
cells. The relevance of t'--e answer to this
question
is obvious. A straightfor-e--d way of getting some
information would be for a =edical research man to
take every opportunity of f -.-a--ticipating in
autopsy
of accident cases, and to ---spect the lungs, and
at
the same time endeavour to obtain as deDendable
in-formation as possible of -.he victim's smoking
habits.
(B) The role of the macrophage :~n the lungs of a
smoker
seems obscure. If they do ~.= fact engulf smoke
pa-rticulate matter they mi,5--'-z be unable to
digest it
in the same way as they do czher organic debris.
It
has been therefore sugges-.e4- that macrophages
containing
smoke material are the car=--*ers of this to the
basic cells.
No one has as yet committe,- themselves to a
clearly
expressed hypothesis, but a useful preliminary
experimental
stem) would be to collect m-acrophages from
healthy smokezs
and investigate whether the- contain significant
amounts of
smoke material.
CD
CARSON et alia Am.N-Y.Acad.Sc. '966 130 (3) 935.
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4. (C) There is some medical which asserts tnat
squamous lung caace:1 i-= jz-edomir-antly found in
the
main bronchi, usually ns-ar to the primary or
secondary
bifurcations, and a different type of cancer,
adenoma,
is found in the alveol-'. If these suggestions
were
ex-ined in detail and result, whatever it may be,
were put on a firm basis this would be of great
imDortance for our studies. The task is not easy
since
by the time a cancer ca7- be diagnosed and located
it
has grown and may have =e-.astisised from its
original
site, but undoubtedly t---e standard of
information at
present available could be improved on. The
immediate
interpretation of such L=formation would staxt off
from
the epidemiological res-.~--t, which is apparently
generally
accepted, that squamous cancers are associated
with
smoking but adenomas are not.
(D) The fourth line of rese-a-sh is currently
being considered
by T.R.C. This is to o'--7ai-n the consent of
doctors to
investigate the sm-okinz abits of such of their
patients
as they suspect may ha=ve lung cancer. This would
involve
not only finding out how much they smoked but the
manner
1 i of their smoking, frequemcy of puffing, ~ow
deeply they
i-ahaled, indeed measuri--E the whole gamut of
parameters
that are open to measuzezent. In the first place
T.R.C.
has remitted this suggez:4-on to the Puffing and
Inhaling
Working Party to report za what facilities would
be
recuired and then it is 7roDosed to ask our
medical
adviser, Sir Johm Richa=dson, on how we should
approach
hospital authorities.
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4. (E) The las-:; line of possible advance is
diff-icilt to
describe short-'y because c;-' the complexity of
current molecular biolog7. It appears that after
several years the centr--- dogma is being
successfully
queried and Ter-ins views aTe being confirmed.
Apparently
an oncogenic virus can _J-7ade a cell and its RNA
can
cause the creation of an ---;-77A-DNA hybrid the
DNA built
up in the cell coding wi~;_', the RNA of the
virus. This
hybrid, inside the cell -=winds in the classical
manner
and the DNA strand leads to creation of a
duplicate
straxid and forms a new dcuble helix. This DNA
duplex
is now stable and can d-i-.'-de in the usual
manner
replicating its DNA. T"hu_z the subsequent
daughter cells
no longer carry their own- hereditary DNA but that
one
embodying the code of the virus RNA. Obviously
there
is szeculation. that this =ay be the mechanism of
virus
induced ca-rcinogenesis.
The imDortance of tkLis is that it supports what
has
gradually become believef_ that cancer may
originate
in a disturbance of th '--asic generative
principle, that
is in a change in the cotfng of the replicating
DNA in
a cell. There is also n:w wridespread sp
-eculation how
this concept mi&lat apply -1o chemically caused
carcinogenesis.1
A number of authors have exDressed the idea that
the step
of "initiation" might be correlated with an action
on
the synthesis of RNA frcz DNA. 2 Nore specifically
Gelboir 3 proposed in 19-6,:i that the chemical
can fix
on the DNA molecule there'--y preventing
duplication of
the portion of DNA to whiz'-- it is attached. Thus
the
hereditazT message passe,_~ an will be altered by
deletion
of Dart of the instructi=s. Alternatively a
foreign
1. MfNTINGS 9, 30UTWE7L Cancer Eesearch 29
510-514' 1969
DIETE-EF PAUL Cancer -'Research 29 121B-1225 1969
2. AIZ-L!_',DROV et alia Cancer _':research 30
1192 1970
3. GELK 7--T Proc.l,'-=,:- -cad. Sc-U.S. 53 1353
1965
C:D
(-Ii
C,
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4. (E) molecule might with a little distortion,
replace
one of the purine or pyrimid-J-e bases and if it
has
a strong hydrog.en cross-bond the helix may never
be
able to u-nz-4-o nast this point. Again there
would be
a permanent loss of a portion of the genetic
instructions,
and since it would affect both strands the
recognized
repair mechanism would be ineffective. In support
of
4
this Falor . believes there is some evidence that
in
human beings chromosomal aberration precedes
histologic
change as the initial sign of malignant
transforma-.ion.
The change in our thinking from a couple of years
ago
is striking and most encourag--*-S. Admittedly
this is
hypothesis but all experience goes to show that
once a
framework of thought about a problem is created
progress
is possible. 11hat happens is that as experimental
facts
accumulate the details of the framework are
amended and
adjusted to accommodate these facts and gradually
the.
whole picture clears. We -see that today the first
hypothetical framework exists, that framework
which
traces a possible pathway from the inhalation of
smoke
in the lungs to the start of a cancer in the
basement
cells. It proposes that some definite chemical
constituent reaches the basement cells by one or
other
f two pathways which are ex-perimentally
identifiable.
The invading molecule "initiates" the carcinogenic
action by deleting some of the Seaetic information
of
the cell, a portion of the im-struction book is
torn out!
If this portion contains some :~=ortant feed back
instructions which are essential to the cells
orderly
4. FALOR Cancer 24(l) 148 1,969
CZ)
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10-
4. (E) behaviour then it is scarcely surprising
that, to
quote Allison,
"A well regulated me!fber of a multicellular
community is transformed into the malignant
maverick that characterizes a cancer cell."
The hypothesis tells us something about the
moleculax
species which does this, either it is capable of
combining strongly with the nucleic acid backbone,
or
it can with a-squeeze substitute for one of the
purine
or pyrimidezie bases but with a stronger hydrogen
cross-bond.
It will be noted that on this hypothesis
vir-,;s-induced
cancer is different from chemically induced
cancer,
and this latter has a clearly defined stage of
initiation.
The cell with the mutilated DNA inst.-actions
could
presumably go on replicating, just wait~mg for the
additional facilities of promotion to jo:Ln in
forming
a growth colony.
This field of research is of such great :Lnterest
to us
that it would seem only prudent to commission some
moleculax biologists to investigate these ideas.
5. CONCLUSION
These considerations show that there is a line of
action
which is within our ability to follow if only we
have the
will. It offers reasonable chances for the
Industry to
emerge with a safer cigarette which will be
recognized as
being just that --- a safer cigarette. However, no
one is
going to do this for us, we must ouzselves accept
this as an
objective and develop a series of steps to attain
it. This
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11 .
5. note has sketched out a set of such ste-ps,
there are
probably better ones, but the important point is
there
must be somme planned set of steps. We car-not go
on
supporting or ourselves carr-
ying out individually good
pieces of research in the hope that in due course
everything will fall into place.
The key steps proposed are firstly supporting the
setting
up of the independent committee and secondly
embarking
on a serious exploration of how human beings get
lung
cancer from smoking. This would involve a number
of
investigations on human beinZs, investigation of
the
chemical interaction of inhaled smoke and mucus,
and
investigation of the molecular biology of chemical
carci-nogenes--s.
No reference has been made to either irritative
effects
or to cardiovascular effects simply because of
priorities.
We are alrea-ly carrying out work in these fields
wh-ich is
promising but work on lung cancer should come
first.
30 th September 1970 Charles Ellis
Z:-
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