DEPARTMENT OF ZOOLOGY INDIANA UNIVERSITY BLOOMINGTON, INDIANA August 6, 1946 Dr. Sol Spiegelman Long Island Biological Association Cold Spring Harbor Long Island, N.Y . Dear Sol: Miss Fisher sent me the material from Lindegren and I have sent my replies back to her. script as well as my discussion with Lirdegren so that you might use this material as a basis for your discussion of the relation of the kappa problem to the theory of gene action you proposed at the conference. You will see that in my answer to Lirdegren I concluded by calling upon you to answer this question. I should be glad if you wuld look over my manu- I too have done some thinkin,p about this problem and I may say, for your information, that I am inclined to believe your theory will pmve to be much more general than the relations we have discovered in Paramecium, although I am still unconvinced that a satisfactory reconciliation between our findings and your studies could be made along the lines that you dis- cussed with me. I should like to have you look back into my paper in the Annals of the Missouri Botanical Garden and think over the remarks I mde concerning the significance of nuclear dualism in Parameciun; for the pro- blem der discussion. I am inclined to lay considerable emphasis on that point. As I pointed out in that paper, I think the fact that we have in the Ciliates a very special situation which makes it possible to have the genes disintegrate in the micronucleus in a way that they could not get away with in cells lacking this particular type of nuclear di- morphism. I should therefore be surprised to find cases like the killer case,in which the gene cannot produce the corres o ding plasmagene,occurr- ing in other kinds of material. The scheme that 93% have proposed seems to me much more likely to be the general mle from my point of view. The very fact that we have this extremely unique situation in the Ciliates provides special opportunities for studying the situation vhen the condi- tions are different from the ordinary, that is, vhen the gene does not produce plasmagene. And the interest is heightened by the fact that we have very closely related varieties of the same "species" in which very likalp your scheme is the one that operates. get your reactions to these suggestions because I think in our discussion we ought to put on record the results of our considered deliberations rather than our initial reactions that we of the conference. I should be very glad to had during the heat LZ I think you are urder t4a~ false impression as to the uncertainty of our knowledge of the self duplicgting capacity of kappa. which you had considered final, namely, what has already been published about kappa, is still the rule and it is important to keep that in mind. The situation -2- What we have done in recent months is to make a deliberate search for really rare exceptional conditions, for I am a great believer in the validity of Bateson's old motto "Cherish your exceptionstt. It is cer- tainly a fact thatpin the overwhelming majority of cases,when K is re- placed by k, kappa disappears very rapidly in tl-e way I have described in my published accounts. we found any apparent exceptions to this and it is these rare exceptions whichwe are now analysing. get our first and preliminary results on the genetic analysis of one ex- ceptional case, and in this case it appears, contrary to my expectat%on, that the genotype of the clone under investigation is actually kk, in spite of the fact that a small proportion of the individuals of the clone remained killer for a remarkably long time before all turned to sensitives. These are only preliminary results and I do not want you to consider them final by any means or even typical of the exceptions. analysis of this mterial and I shall keep you informed of the results. There is clearly something very unusual in these cases ad we do not yet have the clue as to what it may be. The main point to keep in mind, how- ever, is this: cases of this sort are nut typical, they are rare and they may well involve some exceptional conditions which will not only be satis- factorily explained in time but which may provide a means of gaining further funciamental information about kappa. 'de had to make a long and caref'ul search before Since I wrote to you last we have begun to We are proceeding with the I do not know how familjar you are with the history of genetics, but it may be worth while to compare the case I have been discussing with the situation in Drosophila genetics about 1912,- & compare small things with great, At that time the chromosome theory was just getting on its feet. had already proved its value filled,when Bridges &certain exceptional types of heredity which seemed at first to be practically a death blow to the general ideas. his situation also the exceptiorib'results were very rare. The whole matter, however, was eventually resolved when it was shown that he was dealing with a failure of the x chromosome to segregate at meiosis,yielding the condition which we now know as non-disjunction. The exception, therefore, turned out to be actually one of the strongest proofs forthe general rule of chromosome determination. Of course, I cannot be sure that the exceptions I am dealing with now will turn out so happily, but it seems to me that this is entirely possjble. as the type of thing I am now studying should not, for the present at least, be considered as weighty evidence in deciding whether the general rules that have been discussed concerning the self duplication of kair;pa should be held in abeyance. Of course, this is a matter which you will have to use your own judgement on, but I wwdd want you to know the facts fully and also how they appear to me. It y the many predictions that were made and f'ul- In I am inclined to believe that anything that occurs so rarely as Even if others are led to minimize the importance of rrcy early findings, I shall.of course continue to seek out exceptions and analyse them because of my faith that this is good methodological pmcedure. With very best regards and good wishes, Cord i ally yours , 5