In this rather lengthy letter to his brother, Oswald Avery explains that his retirement plans have been placed on hold due
to the war and the recent developments of his research on pneumococcal transformation. The second part of this letter provides
a rather thorough introduction to the history of research on the transforming principle and describes the results of experiments
conducted by Avery, MacLeod, and McCarty and the role of DNA as carrier of genetic information.
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13, 26 May 1943
Avery, Oswald T.
Original Repository: Tennessee State Library and Archives. Oswald T. Avery Papers
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DNA as the "Stuff of Genes": The Discovery of the Transforming Principle, 1940-1944
Studies on the Chemical Nature of the Substance Inducing Transformation of Pneumococcal Types: Induction of Transformation
by a Desoxyribonucleic Acid Fraction Isolated from Pneumococcus Type III (February 1944)
Studies on the Chemical Nature of the Substance Inducing Transformation of Pneumococcal Types: II. Effect of Desoxyribonuclease
on the Biological Activity of the Transforming Substance (January 1946)
Studies on the Chemical Nature of the Substance Inducing Transformation of Pneumococcal Types: III. An Improved Method for
the Isolation of the Transforming Substance and Its Application to Pneumococcus Types II, III, and VI (January 1946)
Letter from Oswald T. Avery to Roy Avery (partial transcription) [13, 26 May 1943]
Appendix I: A Letter from Avery to His Brother Roy, Dated May 26, 1943 (1976)
Thanks very much for that good letter--of course, I understand why you couldn't make the party the boys gave in my honor.
Naturally they didn't tell me that you or other guests outside the department had been invited--it was all to be a surprise.
It would have made me very happy if you could have been with us that evening--Ernest Stillman and Ken Goodner simply told
me that they thought it was about time the past and present members of the Staff--all the "57 varieties" of pneumococci,--got
together and had a reunion. I said I thought it a good idea but doubted whether the men could get together these stern and
busy days--and perhaps it would be better to wait and not attempt it now. I was over ruled--they pointed out that it was good
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[BEGIN PAGE TWO]
have a reunion--buck up morale--a little diversion, times like this, was just what we needed. So the plans went on and I was
not consulted further. And they did come back--Dr. Cole and "Do" were there--Francis Blake from Yale, Alan from Balto,
Dubos from Harvard, Tommy Francis from Michigan and others. They had invited Bill Parke with whom I roomed four years at Colgate,--but
he was sick in bed with Grippe--sent me a nice letter. There were about 35 men present, and it was quite impressive to see
the old boys come back--and to realize how they had advanced not only in years but in rank and position.
The boys in the Department wrote some topical verse. Bill Tillett was master of ceremonies and the whole occasion sparkled
with wit, skit, and jovial good humor--happily, at no time sinking into lugubrious and doleful speeches;--bright cheerful
and happy it was throughout--I really enjoyed it--
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and appreciated not only the spirit which prompted it but the spirit in which it was done--an altogether happy occasion. It
brought back memories of 30 very happy years spent in a stimulating environment and an association with a splendid group of
men to whom I owe far more than they know or can ever realize.
Last Friday evening (May 7th) I dined with Dr. Goodpasture--We were attending the Board meeting in the Surgeon General's
Office in Washington--Ernest asked me to have dinner with him. We had a delightful talk together. He brought messages from
you--and we discussed my future plans--about the possibility of my coming to Nashville. What a joy it is to me to know the
depth and sincerity of that welcome--it means much to me these days--If this War wasn't on I tell you frankly I would
liquidate my affairs here and start for Nashville this fall.
! ! ! (Lapse of 13 days--Letter started again May 26)
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May 26. 1943.
Almost two weeks have passed since I began this rambling letter--I shall attempt no explanations save to ask to believe that
I have not been wholly idle in the meantime or unmindful of you and those I love in Nashville--
Indeed, I have been busy--just manage to keep my head above water these days--Come home each night determined to catch up
my letter writing but a hundred and one other things barge in until it's so late and I'm so tired and sleepy I postpone,
go to bed, resolving to get up an hour earlier in the morning--of course that's fatal--as the present results show.
Now as to some work I'm doing in the Lab--and I speak of it because I know you'll be interested and also because it
bears on my future plans and my wanting to liquidate my affairs here and spend the rest of my days with my family--as I mentioned
at the bottom of page 3. As you know on July 1 I relinquish Chairmanship of the Department and retire from active membership
of the Institute. Both
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Dr Gasser and Dr Rivers have been very kind and have insisted on my staying on--providing me an ample budget and technical
assistance to carry on the problem that I've been studying. I've not published anything about it,--indeed have discussed
it only with a few--because I'm not yet convinced that we have (as yet) sufficient evidence. However, I did talk to Ernest
about it in Washington and I hope he has told you--for I have intended telling you first of all. I felt he should know because
it bears directly on my coming eventually to Nashville.
It is the problem of the transformation of pneumococcal types. You will recall that Griffith in London, some 15 years ago
described a technique whereby he could change one specific type into another specific type through the intermediate R form.
For example: Type II --> R --> Type III. This he accomplished by injecting mice with a large amount of heat killed
Type III cells together with a small inoculum of a living R culture derived from Type II. He
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noted that not infrequently the mice so treated died and from their heart blood he recovered living, encapsulated Type III
pneumococci. This he could accomplish only by the use of mice. He failed to obtain transformation when the same bacterial
mixture was incubated in broth. Griffith's original observations were repeated and confirmed both in our Lab and abroad
by Neufeld and others. Then you remember Dawson with us reproduced the phenomenon in vitro by adding a dash of anti R serum
to the broth cultures. Later Alloway used filtered extracts prepared from Type III cells and in the absence of formed elements
and cellular debris induced the R culture derived from Type II to become typical encapsulated III pneumococcus. This you may
remember involved several and repeated transfers in serum broth--often as many as 5-6--before the change occurred. But it
did occur and once the reaction was induced, thereafter without further addition of the inducing extract, the organism continued
to produce the Type III capsule; that is the change was hereditary
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[BEGIN PAGE SEVEN]
and transmissible in series in plain broth thereafter. For the past 2 years, first with MacLeod and now with Dr McCarty--I
have been trying to find out what is the chemical nature of the substance in the bacterial extract which induces this specific
change. The crude extract (Type III) is full of capsular polysaccharide, C (somatic) carbohydrate, nucleoproteins, free nucleic
acids, of both the yeast and thymus type, lipids and other cell constituents. Try to find in that complex mixture the active
principle!! Try to isolate and chemically identify the particular substance that will by itself when brought into contact
with the R cell derived from Type II causes it to elaborate Type III capsular polysaccharide, and to acquire all the aristocratic
distinctions of the same specific type of cells as that from which the extract was prepared! Some job--full of heartache and
heart breaks. But at last perhaps we have it--The active substance is not digested by crystalline trypsin or chymotrypsin.
It does not lose activity
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[BEGIN PAGE EIGHT]
when treated with crystalline Ribonuclease which specifically break down (Yeast nucleic acid. The Type III capsular polysaccharide
can be removed by digestion with the specific Type III enzyme without loss of transforming activity of a potent extract. The
lipids can be extracted from such extracts by alcohol and ether at -12 degrees C. without impairing biological activity. The
extract can be de-proteinized by Sevag Method--(shaking with chloroform and amyl alcohol) until protein free and biuret negative.
When extracts, treated and purified to this extent, but still containing traces of protein, lots of C carbohydrate, and nucleic
acids of both the yeast and thymus types are further fractionated by the dropwise addition of absolute ethyl alcohol, an interesting
thing occurs. When alcohol reaches a concentration of about 9/10 volume there separates out a fibrous substance which on stirring
the mixture wraps itself about the glass rod like thread on a spool--and the other impurities stay behind as granular
[END PAGE EIGHT]
[BEGIN PAGE NINE]
precipitate. The fibrous material is redissolved and the process repeated several times. In short, this substance is highly
reactive and on elementary analysis conforms very closely to the theoretical values of pure desoxyribose nucleic acid (thymus
type). Who could have guessed it? This type of nucleic acid has not to my knowledge been recognized in pneumococcus before--though
it has been found in other bacteria.
Of a number of crude enzyme preparations from rabbit bone, swine kidney, dog intestinal mucose, and pneumococci, and fresh
blood serum of human, dog and rabbit, only those containing active depolymerase capable of breaking down known authentic samples
of desoxyribose nucleic acid have been found to destroy the activity of our substance--indirect evidence but suggestive that
the transforming principle as isolated may belong to this class of chemical
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[BEGIN PAGE TEN]
substance. We have isolated highly purified substance of which as little as 0.02 of a microgram is active in inducing transformation.
In the reaction mixture (culture medium) this represents a dilution of 1 part in a hundred million--patient stuff that--and
highly specific. This does not leave much room for impurities--but the evidence is not good enough yet.
In dilution of 1:1000 the substance is highly viscous as are authentic preparations of desoxyribose nucleic acid derived from
fish sperm. Preliminary studies with the ultra centrifuge indicate a molecular weight of approximately 500,000--a highly polymerised
We are now planning to prepare new batch and get further evidence of purity and homogeneity by use of ultra centrifuge and
electrophoresis. This will keep me here for a while longer. If things go well I hope to go up to Deer isle, rest awhile--Come
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[BEGIN PAGE ELEVEN]
refreshed and try to pick up loose ends in the problem and write up the work. If we are right--and of course that's not
yet proven, then it means that nucleic acids are not merely structurally important but functionally active substances in determining
the biochemical activities and specific characteristics of cells--and that by means of a known chemical substance it is possible
to induce predictable and hereditary changes in cells. This is something that has long been the dream of geneticists. The
mutations they induced by Xray and ultraviolet are always unpredictable, random, and chance changes. If we prove to be right--and
of course that a big if--then it means that both the chemical nature of the inducing stimulus is known and the chemical structure
of the substance produced is also known--the former being thymus nucleic acid--the latter Type III polysaccharide and both
are thereafter reduplicated in the daughter cells--and after innumerable transfers
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[BEGIN PAGE TWELVE]
without further addition of the inducing agent, the same action and specific transforming substance can be recovered far in
excess of the amount originally used to induce the reaction--Sounds like a virus--may be a gene.
But with mechanisms I am not now concerned--one step at a time--and the first step is, what is the chemical nature of the
transforming principle?--Some one else can work out the rest--Of course the problem bristles with implications. It touches
the biochemistry of thymus type nucleic acids which are known to constitute the major part of chromosomes, but have been thought
to be alike regardless of origin and species. It touches genetics, enzyme chemistry, cell metabolism and carbohydrate synthesis--etc--But
lately it takes a lot of well documented evidence to convince anyone that the sodium salt of desoxyribose nucleic acid, protein
free, could possibly be endowed with such biologically active and specific properties, and that evidence we are now trying
to get. It's lots of fun to blow bubbles--but it's wiser to prick them yourself before someone else tries to.
[END PAGE TWELVE]
[BEGIN PAGE THIRTEEN]
So there's the story Roy--right or wrong it's been good fun and lots of work. This supplemented by war work--and general
supervision of other important problems in the Lab has kept me busy, as you can well understand.
Talk it over with Goodpasture but don't shout it around--until we're quite sure or at least as sure as present method
permits. It's hazardous to go off half cocked--and embarrassing to have to retract later.
I'm so tired and sleepy I'm afraid I have not made this very clear--but I want you to know--and sure you will see
that I cannot well leave this problem until we've got convincing evidence--Then I look forward and hope we may all be
together--God and the war permitting--and live out our days in peace. What a lovely picture of dear Margaret. How is she and
Cath--wish we could all meet in Deer Isle. I know Minnie has kept you all posted--Things go well with us despite the cruel
war but Victory must Come and I'm optimistic enough to
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to look forward to happier days even if they are not perfect--we can take it--and still be happy.
Forgive this rambling epistle--with it goes my love and thoughts and the hope of better things ahead--
"With heaps and heaps of love"
Affectionately and Faithfully
If the Board in the Surgeon General's Office meets at Camp Bragg as I think they may later on I shall take the opportunity
of running over to Nashville for I want to talk over future plans and possibilities with you and Catherine. Do write if just
a line--I want to know your reaction--and don't hesitate to talk to Ernest, he knows it all and we talked it over very
Good night--it's long after mid-night and I have a busy day ahead--God bless us, one and all