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. CONFIDENTIA,iTY AGREEMENT. tEpORT ON SITE VISITS AT UNIVERSITY OT SAWIII AND UNIVTJISITT 0? COLORADO, fOULDER, T[DRULL'i 12-13, 1975 turpo a of Sesaarch: To investigate a possible b.r.ditA:ry factor in the tobacc fsokinS habit and possible strain diffarences in anisal raspoaaes to nicotina, and other tobacco components; and to correlate the b:aan and asiaal observations by intsrdisciplinary studies. Institutions and Investigators: The huaan studies proposed are to be carried out in kavaii, involving populations of IIwaiian, Caucasian and Japanasa origins; art in Europe, includint Sv.dsn and possibly Balgium and 8olland. The anisal axperisents are planned to ba carried out at the University of Color 3oulder, in the institute for Sabavorial Genetics (I3G). The overall director of the proposed pro=raa is Prof. Gerald L. KcLsarn, Direct of ISG. Tba senior invsstigator in Yavaii is Trof. Geoffrey C. Asbton, Prof. of Genetics and Asst. Vice Chancellor, University of Rsvaii. Other maamlers of the tea= are given below and in the critique. . DudSet: Lstiaated at $800,000 per Taar for about S years. See recomendation for business manaSer position to be added, in the critique. fackground of Invsstijations: Prof. Aahton has baan engaged in a cognitive study in Eavaii, testing farllies of different racial stocks for possible differsnces of genetic and snvironmental factors in various mantal functions. About 1,400 faailiss have been tested, and there is available a cooperative group of over 2,500 psrsons who can be invsstigated for their smokiaS behavior and its social, economic aad psychic correlations by faa:ily Sroups. The parents and children, including an average 2.8 brothers and sisters, are to be studied for smoker versus nonsmokar differences. In this test pool already available the children are 25 to 30 Iu rs old, and o„ familias can be tested per yu r. 3esides the questionnaires, height and weight, blood pressure and blood sasspla tests for over 25 itsas that segregate genetically i bumans are planned. This is useful in confirsinj the family relationships, and in ssarchin: for =enatic linkages vith differences in ssoking behavior. In groups of this size statistical analyses now available permit segregating groups, pointing to the degrees of environmantal or genetic bases for observed differences, and the possible associations of smoking to other known genetic traits. As the accumulatsd data beco.e sufficient it would be feasible to test groups o people who show genetic attributes of smokers but who for religious or other reasons do not smoke, such as the large Mormon population.in Esvaii. Their susceptibility t disease and their other characteristics would be relevant to the Tiabar hTpothesis that certain people who ssoke .ay also be genetically sora susceptible to develop certain dissases, an important theory not so far adequataly investigated axperinenca Sus+an genetic studies now are strengthened by the use of tvins or half-brothers and half-siaters, who had one parent in cossion. Drs. David W. Cruspacksr, Steven G. Vanderberg and Prof. Jaaas S. Williass (Colorado State Univ.) bav" contacts in Svell 3algium and Holland that offer the possibility of collecting groups of tv-ins, hal°.~ brothers and half-sisters, and married ralativss. These vtll include a living gta:,;, parent, a comon parent (male or f eaale) who married tvics and Sad tvo sets of offs"~ or who surried and had tvins (either identiul or not), who in turn had children. is thought possible to find 300 such families and intarviw over 2,500 persons in Europe, old enough to have had an opportunity to begin smokinj. The advantages of the European studies are the different racial origins, the better access to tvin and fa¢ily information, and less cagplications of obcainir.g irn views. The best locations and populations in some or all of the European coucci:es ^:till need to be determined. - The ani¢al studies at IbG. Univ. of Colorado, Doulder are planned on an excer.si auperimental background of different animal responses to alcohol. It has been poss: CTR 1 1 N 0G. L7: "1' GED

r -2 THIS DCCUrA VIT to distinguish ouse strains that either prefer or avoid alc~~~'ic'.d:vYcMatlnRisg water, and nice that either sleep a long or a short tise after the same doses of alcohol. This in turn has led to studies of the biochemical differences in brain sensitivity, vetaboliso and tolerance developaent to alcohol. It is proposed to use the teas and .ultidisciplinary approach in investigate comparable differences in response to nicotine, either injected, ingested or (lacer) inhaled as tobacco asoke. Nicotine acceptance or aroersion by inbred a+ice and substr, vill at first be studied by fivs sajor approaches: 1. Dr. iaibart P. Alparr, from tt .ievpoint of affects on learning and memory. 2. Dr. Thilip M.'Gro.es, in relation tc effects on neuronal activity, particularly in chronic axposure, with or without a-- phetamine. 3. Dr. Xurt Schlesinger, coneerned with genetically detersined biochemici .echanisms affecting nervous excitability and seizure susceptibility. 4. Dr. Seth K. Sharpless, use and disuse (drug dependency) and neuronal excitability. This is testc by souse brain waves, iacludinj special socalled theta rhytha from the hippocaaus, activity of vhich is proe+otad by nicotine and appears dose dependent. S. Drs. Schlef and Sharpless, study of tissus cultures of neuroblaatoaa, a serve call cancer that differentiates under certain stiauli. Soese nicotine studies of asice or rats rill involve iadvelling catheters for iatarnittent nicotine injection. Later uae of asokin= sachines is planned. These animal investitations with Dr. McClearn's direction involve an unusual anc probably unique group of young collaborative workers who genuinely integrate their findings. The results of the aniaal studies can be analyzed by existing saethods for possible single Senas or polygenes correlated vith differences in nicotine acceptanc( and responses to it. •etwen the animal studies and bu:an studies the integration planned is facilit: because the senior investitators are on both the Hawaii and Colorado university fac- ulties. Information found in anisal studies will flow proeiptly to those collecting buman data. Certain souse social interaction tests in use may suggest additional questions to ask humans. If the human studies suggest the prenatal environmenc is important, then certain prenatal anisal experimsats would be desirable. Critique: A grueling site visit and interrogation of over 2 working days was conducting b~ Dr. Willias Gardner (Chairman), Drs. Jases Crov, Univ. Wisconsin; John Fuller, L'r.iv. Dinghamton, N.Y.; Henry T. Lynch, Univ. liebraaka; and *yself. Mr. Edvin J. Jacob served as liaison and technical advisor. A11 those listed above were questioned at length, and supplementary documents and literature citations and reprints were pro- vided. The animal facilities and laboratories at ioulder were visited. The reviev o: the proposal, background, possible yield, additions and deletions, professional coc;• stance, university acceptance, achievability, publishability, technical and equi;ne::! support, budget and overhead was eQually or sore thorough than carried out on r:H or CTR site visits. My conclusion is that this is rasarksble opportunity to find out the degree of Senetic influence upon the nokinS habit or nicotine. The aniaal studies offer app:: tions of rather povarful nw techniques to the question of nicotine effects or brairn function at the subcellular, cellular, regional, inte=rationa.l and total anir.al a::- ivity levels. The group at foulder is unuaua1.17 talented. asbitioua and collabora- tive - a rare type of research teaa+. No question exists but they vill do the jo~. The human studies in Hawaii and Europe, while not so advanced in science (ref:ec ins the state of the art) offer an attractive gamble. If soe+e part of the smoking public inherits this tendency, and their sedical data are later collected, the facts vhatever their nature likely vould revolutionize the general scientific attitude in t field. If no human genetic aspect is found, the search will have, for once. been ca: on a sound modern basis. What are the negative aspects of the program as a whole? I am a little sKepcic: of Prof. Ashton's wholehearted co=itment to this subject and cannot evaluate :`.e i-• dependent drive for success of his subordinates. Second, the human studies are a f:• 'ng expedition without predictability of success or failure. The European cr::=^. s• S920 IkN l I CTR HN 028466

I . -3- THIS DOCUM,';T :'A;E-7 T) CONFIDENTIAUTY AGREE,HENT. ever uatariali:e in large enough num,bers for good statistical aailysia. Third, Prc: Kk Claarn is a roaarkible organizer and leader, and should sosathin: happen to him tt protram silht lose its present elegant focus and cohesion. Sovevar, Prof. Villiams, who is the proponent of turopaaA studies, isakes an un- uauall] good iaprasslon. In this kind of funding the sen and tbs place and the potential saes more crucial to success than the forsal protocol and tha exact budget breakdovn. It is astonishing how the project proposal evolved between our first interview last fall and the site visit. This argues continuing evolution, refinemer and isprovamant after it is funded. I as laft with full confidence in the ability o Dra. KcClearn, Wiliitas, Crssspackar, /llpern, Sharpless, ScbesinSer and Groves to •chieve significant scientific progress in this field. I believe at the budget proposed this program is so.evhat of a bargain, overhead 10 percent for instance. At tQe vary least anisal strains sensitive or insenaitiva to nicotine or rmoke say be expacted, as vell as a biocheaical explanation of the differences. This vou: be a real advance. Tinally, unlike sose other industry appropriated funds to instit this pro=ram will vitbout doubt provide a base of haovla=e to build on. I do think Prof. McClu ro should be allowed a budgeted business aanaSer at $15,000 to $35,000 per year to handle the sos+avhat complicated finances. I enthusiastically racomand the approval and funding of this proposal. The monitorinS and review of progress at certain intervals I would leave to Dr. Gardoer' advice and proposal. Respectfully submittad, Sheldon C. Somers, M.D. I lN 5321 1 CTR HN 0284617