Carcinogenesis: Chemical, Physical and Biological

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Carcinogenesis: Chemical, Physical and Biological
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she's. to. well. and thank you professor folks. ladies and gentlemen. the title of the the discussion as it was given in the program. it is a carcinogenesis chemical physical and biological the concern for this subject is one of very broad character yesterday you heard the. a call for the scientific community to.
be concerned with matters of public interest. well this won it is such a watt in our country well first of all we are all surrounded by what seemed to be a variety of agents in our environment. which may in fact in some cases we know do they have serious consequences for human health.
these include many of the natural environment all agencies such as ultraviolet radiation from the somme are icing radiation either from outer space are from the earth's surface are created by man. and of course a wide variety of chemicals some created by the needs of mankind. some existing n.h. are in ordinary foodstuff us.
now as professor folks a said a moment to go it's so it seems a far cry from the work which he described on photosynthesis to the subject upon which i chose to talk today. in a sense it is in another sense it is it. after all the kinds of questions which a we sought answers to one we undertook to determine our to try and find out how a green plant uses sunshine to manufacture food and material.
called the use of all sorts of all branches of all disciplines of science are getting chemistry physical chemistry physics by chemistry and biology. and later as a i found in the last few years even as such matters as.
human behavior and economics. this subject is a similar won in that sense in that it involves all kinds of human knowledge. and that the specific way in which i came to be involved in this is something that perhaps at least some of you will appreciate. about. all four years ago all that came into my laboratory in berkeley a young man and the taliban who was so had had a person know what is organic chemist and had a personal experience with the disease and cancer.
as a result of that he said. applied for and received a postdoctoral fellowship it from one of the private agencies that exist all over the world particularly dedicated to the problems of cancer. he also was much interested in working in our book the laboratory because some of his friends had been there before him and had told him a little bit about the place so when he arrived his fellowship specified that he had to work on cancer.
but we had nothing going in the laboratory on the subject specifically so we had a conference or calais and i sat down he came into office we discussed what could be down that would fulfill the requirement of his fellowship and my interest.
and after some discussion we agreed that the photo chemistry are some carcinogenic agents in the environment would do this and that is how in detail a specific detail we became involved. in the problem that was the beginning of it and you see that's the nature of our lives moving from thing to say from adjustment to adjustment and expanding always expanding our interests by virtue of the flux of young people which goes through our.
the laboratory. it is the thing which if a i hopefully believe his soul that keeps us alive in that particular group of workers. when our without falling that line without trying to give you the details of what are called i did and how it expanded into what i'm going to discuss today out point out what he did as we go along now why is this subject relevant as i said earlier.
where there are a car surgeons various kinds of them physical chemical and biological surrounding us all the time the chemicals which a we add to our food which we uses drugs and with which we are in contact every day either in our clothing or not furniture. her or in our houses contain materials some of which might be and fact are known to induce the appearance of tumors in met the only way in which this kind of relationship is established is by an epidemiological study.
don't do experiments with men usually and it's interesting to remind you that the earliest known such connection was discovered by a british physician an almost two hundred years ago in the case of the chimney. sweeps who cleaned out of the chimneys of british calls you know each year they collect a lot of soot from the coal that that were burning and these to be super have to go through those japanese and sweep them out turned out that there was a particular kind of.
cancer cancer of the scrotum which was very prevalent amongst these people and eventually that cancer was traced to a chemical contained in the soot which collected in the chimneys and this is the one in fact one of them with which i will spend.
and most of my time there are many other such materials not that we know about a career in our food or and our environments. the other end of the story was not only do we have a wide variety of carcinogenic is that is chemicals radiation and biological materials the most recent of which has a and you've heard about it here before our the viruses the.
not so the consequences of their action the way in which the carcinogenesis is expressed varies a great the depending upon that part of the body in which the cancer appears it looks very different from one to another so we have a wide variety of agents. very different in character and we have what looks like a wide variety of consequences also very different in overt appearance however it is my belief and it is going to be the thrust of everything i say this morning that this wide variety of agents.
act through a single kind of mechanism not one mechanism a single kind of mechanism and that the wide variety of expressions of the consequences of the biological consequences are all of the same general sort involving a change in. and the genetic content of cells and the expression of that change of genetic content may be in a variety of forms but have one thing in common.
and it is this commonality between the inducing agents on the one hand and the consequences on the other that i would like to bring into one story if i can now as an example. yesterday at lunch i was reminded of a story are a bit of advice which i frequently find myself in dues to give to some students and what i'm going to do today and going to say today is really the end.
saddam and of that advice. very often a student will arrive or work in the laboratory and spend his entire time gathering data without really trying to integrate it saying that while he doesn't have all of the information and he's going to wait until he has collected it. all before he begins to think about it.
now this isn't really the way science girls is true that without data a science can't exist or can't continue can't develop but it isn't really the way in which a new generation of thought is created at least not in my experience and i have to. tell them a little story i do it in this way i say to them it is not it in order to be creative in science one must take asian only not always in fact very seldom get the right answer but occasionally must get the right answer about how nature is working when you only when you have only.
half of the data in your hand and half of what you have is wrong and you don't know which half his rock and then you get the right answer you're doing something create. and that's what i'm going to do today. i haven't got all the data some of what i have is wrong but i don't know which parts of it are all i'm going to try and put it together and eventually there will emerge from this construction certain kinds of course.
actions which one can put to the experimental questions which one can put to the test and as we put them to the test we will modify our concepts to fit so that the new concept changed by the new information grows eventually into a correct one. knowledge is going on with the nature of chemical carcinogenesis as we understand it today course it was my change but today there is a basic unity at least appears to be a basic unity in the nature and the chemical nature of the.
since his which are known to be carcinogenic produce cancer either in man or an experimental animals or more recently and even simpler systems such as cultures of living cells in a bottle in a flask from various sorts.
of animals and still simpler systems in which we test the chemicals on certain relatively purified enzyme systems which are molecules themselves and so we have a range of tests systems from the whole animal on the one hand what mankind on the one hand. to animals to tissue cultures to molecules and we do all of them. when we look at the collection of molecules which we know to be carcinogenic in one way or and at in one system or another we see that there is some commonality in their construction and the first slide is simply a catalogue of such chemicals all of them.
have one thing in common they all produce electoral flake gets this car born in milan this come on in mind when the carbon to oxygen bond is broken the negative charge means on the oxygen the positive on the carbon and this car bomb in mind then is an electoral philip agency king a high. density of electrons and this is true of the all of these first for that i've put on the black on the slide machines are all of them are alkylate ing agents electra filigree agents giving a positive carbon atom even without any interest the enzyme interference and the kind is.
of electron tense molecules which they react i listed over here in this column and for the those molecules which of which are common in cells the electoral file i should say the nuclear files are mostly nucleic acid bases either in d.n.a. or an iron a or in.
cruelties or maybe others as well these are the principal ones that are seen to be involved in the change in the genetic composition of the cell there are a number of other molecules listed in the lower half which by themselves are not elected files at least not from their first look however. after they are changed into magically this one by oxidation of this n.h. bond to an end all wage bomb which then can be a sarah five with acetate herself eight and this now drops off as a negative i and leaving behind a positive nitrogen iran which in turn can be and it is.
a powerful electrified just as this company mines are the same sort of system occurs same sort of change occurs on this carcinogen which used to be used as a food coloring many many years ago is no longer so used it was found to be a carcinogen of the liver but it and it and it's the. second is some of its transformation from this yellow die into a carcinogen is probably very much the same as this one here by oxidation of the nitrogen to an end a wage and then eventually getting into a night tony mind so that it can attack the cellular nuclear force the same thing can be said of these nitrogen compounds.
now down here there is a very simple sambol p. h. meaning polly cyclic aromatic hydrocarbons and these require enzyme activation and when they are so activated they also appear to be nuclear.
fox and it is this group of compounds about which i will speak mostly in terms of the chemical consequences that group of compounds the particular example of which is shown in the next slide. all are produced are i should say are produced always went any combustion of any organic material occurs for example one you burned to tackle in the cigarette some micrograms of benzo a pyre in the one on the left is produced.
when you burn gasoline in the internal combustion engine some milligrams of then so a priory are produced and come out the back end of the exhaust pipe when you burn coal in a park plant or in a heating system and all a good bit of this policy. the cyclic aromatic hydrocarbon is part of the combustion products and so that particular group of calm pons finds its way into our environment in many different ways even when you burn wood are i should say agricultural refuse as a result of the harvesting.
what are the pruning of treats this also is one of the products it's comes out in the small and so it is a common environmental component it is perhaps most effective what it is inhaled into the lungs as a result of smoking a cigarette but because and it gets. right to the sensitive tissues and so the very few micrograms from each cigarette are deposited right in the proper place a few life not the basic notion about how this material which is a relatively inert it seems to be a relative.
the entered chemical these police i take aromatic hydrocarbons how can they become how can they be made to fit into the notion of electoral flick activity which we mentioned a moment ago. in the last decade a great deal of work has been done implicating and enzyme system which is present in all living cells to some extent but is induced to a higher level in cells and most cells particularly liver when they.
are exposed to such materials as this not only this one but other materials have the same kind will do the summer think these are called for obvious reasons the aerial hydrocarbon hydroxyl ways as a group of mixed function oxidase. is it is enzymes which will use molecular oxygen to add one of the oxygen atoms to the aromatic hydrocarbon and used to hydrogen atoms from my reduced cohen's i'm to take care of the other oxygen atom this is what is meant by him.
mixed function oxidase their president more cells and tissues but there are rays to a higher level when such cells and tissues are exposed to these aromatic had two cars were now the next slide shows a way in which that happen.
ones aromatic hydrocarbon hydroxyl a's and molecular auction and i didn't put down here the reduced period the nucleotide which takes the other oxygen atom and it was proposed that one of these oxygen atoms is used to hook on to the aromatic hydrocarbon in the number three and four position making. in this epoch side now that's a very unstable compound which with a little bit of acid opens to give a car body of mine at one of these positions either that one or that one which then will react see divide up so and the remaining qurbani mind will then react with the nuclear file giving the.
carbon to carbon bond which i mentioned at the beginning the us this is proposed as an obligatory intermediate to make this compound into an electro far which can then be carcinogenic if this reaction occurs a side reaction which destroys this is simple hydrolysis. of this epoch side linkage to give a dial.
there are many lines of evidence which indicate that this hydroxyl a's is indeed involved in making this compound into a carcinogen if one box this enzyme in some way either by a chemical agent which blocks it or by a mutation which prevented. from being made this material then does not become carcinogenic in such cells so the participation of the hydroxyl ways seems to be well established however the isolation of such a product has never been a cheat and so we don't really know whether this is indeed away.
the in which the hydroxyl a's produces its effect and it was at this point that the student whose story i told you earlier on entered the picture he undertook to examine the reactions of these aromatic hydrocarbons with components of nucleic acids. and the one he chose was an methyl cytosine and the next live shows what he found instead of finding the hydroxyl a compound on the three or four position he found that the reaction took place on the number six positions on the four five edition reaction took place not here but on.
the number six position to give this product now this is a full of chemical induced coupling however the same reaction can be induced with the arrow hydrocarbon hydroxyl a's and oxygen exactly the same reaction in which one gets this kind of a coupling rather than nose on. the six position or on the won and the three one three or six and not on the floor and five and that was his contribution then to this business.
well now we have the us examined the chemical behaviour of a number of carcinogens this one in particular but as yet we have no clue as to what the biological consequences of such an event might be why if this happens even if it happens why should that. produce the biological consequence is that we know it produces namely cats.
now here i have to leave chemical carcinogenesis well what i was also one more word about it but we're going to leave karst chemical carcinogenesis for a moment and examined what we know about biological carcinogenesis and then after eight describe to you what i think is the nature. future of biological carcinogenesis we will see if we can't put the two things together and make a single unitary concept of the whole thing. before we leave this chemical reaction like to see if we can't imagine what the molecular consequences at least have such a change would be now i'm going to i don't have pictures of and i don't have a model it's a much too big to carry from berkeley to lend are so i'm.
going to ask you to imagine this thing most of you have hurt of the structure what the structure of the genetic material of living things is the nucleic acids either the d.n.a. or the on it most all mammalian of all animals have d.n.a. as their principal.
storage material for the genetic information and that this d.n.a. is primarily first constructed as a sequence of bases of which that n.f.l. cytosine is won or that cytosine is one set of the methyl groups his rivals sugar there and it is a long string of such. cases of which there are four different kinds the side to see is only one of them there are three others but all have similar kinds of electoral of electron dense materials in they wind up in the double helix structure which you all heard about in which the bases are stacked like like playing cards one.
on top of the other three and a half in streams roughly three having strums apart now if this aromatic hydrocarbon were to it slip in between some of these bases and form that kind of a coal vaillant carbon to carbon bombed as it is described year this a carbon atom and that's. the carbon atom if this were to happen in the double helix the normal helix structure would be distorted in fact one could not maintain it if that reaction occurs and the normal helix structure would be distorted so that at least one of the.
the linear molecules would be looked out that could not fit in the double helix it would have to be looked out as a sort of a loop outside of the double helix at least that perhaps more that is a molecular consequence of such a reaction and at the end of this conversation i will try to do. dose or introduce that again and go from that to the biological consequences of such an event but before i can do that we have to examine what we know or what we think we know about the way in which a virus can induce cancer can change.
the age the character of cells to make them into malignant cells now most of the work we have done in berkeley at least in my laboratory that is has been knocked with whole animals all we've done some of that and i will show you the very last sides of that but mostly it has been done either.
with enzymes isolated enzymes and more recently with cells either animals growing in tested in a tissue culture and we examined the behaviour of those cells under various influences on the viral influence under chemical influence and under both in order for you. to get some idea of how this is don i want to show you a picture of a tissue culture of mouse cells which have been infected with a virus and wherever the virus particles have have been introduced into the cells and have transformed them.
whatever mechanism and will come to that moment those cells which are transformed shoal as little piles of cells and the next side shows that tissue culture in which a field of the cells had been transformed on the left we have only a very weak magnification only a ten fold magnification. and the dividing line is right here this background is a background of normal cells cells which have not been infected with virus and which grow to confluence and then stopped growing that is when they touch each other when all the cells are touching each other they signal each other.
are they send signals to each other in such a way that the growth of the cell stops however those cells which have been infected and transform by the virus he said com a virus no longer are subject to that control mechanism and they even though they.
i'm to confluence to touch each other they keep on growing and pile up on top of each other and these little piles are called for side and there are visible in this picture one large focus and another smaller one and still to more smaller ones there as i said i think for. course i hear one large one and three small ones in which the piles of cells are visible even to the naked eye when hardly needs a microscope. this is the same picture blown up forty times a set of ten times this focus plus that one you see it is and each one of these little bright spots is a rounded up cancer cell piling up on top of some or and you see that the me the big focus which is that one and then at the edge of.
the smaller one here this kind of system is one which has been widely used in the last decade to explore chemical viral and radiation carcinogenesis rather than using whole animals one of the reasons for this is one can roll a million cells on a dish only three.
centimeters in diameter if one had to grow do similar statistics with a million animals even mice you can imagine what kind of a housing problem that would be well this has facilitated the work in not enormously and it is this kind of tissue culture work which is dumb.