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REPORT NEW ENGLAND INST'I'h[JTE FOR MEDICAL RESEARCH RIDGTiFIELD,, CONN. March 1963 &IHENew England Institute for Medical Research was ,ffouadmdd in 1q54' to engage in basic research incorporating odLer saecncM with saaedidne and' biology in order better to understand the cause andd cure of disease. 'Normalcy or disease occurs at the level of the molecules in cells of the human body. Only by understanding how molecules function in cells, and body fluids can we understand and over- come disease. Molecular research has, been greatly advanced by discoweries of recent decades in physics, chemistry, vnathematics and elec- tronics, each adding significantly to medicine and biiology., This approach - ternned' "'interdiseiplinary„ ba:sic research - becatne andl reimains, the foundation of the Institute's work, which is„ therefore,: largely different in nature from applied re- search or research limited to one field. Since basic research at the Institute i's conducted at the moldc - ular level un derlying all lifc, its findings are prowing useful in numerous other fields of science. Highlights of work at the Institute since our previoius report of March 1962 are noted on following pages: - JOHN H. HELLER, 11+I.D: aecw'iTre LasracAor. The Trustees of the rrlewR England Institute for lNedicall Research cordiallly invite your inquiry into: its work, preferabl~y by: a personal visit, so that you will be in a better position to recognize its rmerits and need'x Speciall group meetings: can be arranged for daytime or eveni'ng. Gifts, grants and be- quests tm the Institute qualifx as charitable contiriibutions under f'ederall t'ax. laws.

SOME OF'I THE CURRENT RESEARCH AT THE' INSTITUTE RF' Effects ors CeUs and Cbrowsows. 40 WAVS pulsed so as to, reduce thermal effecs, have powerful effects on living cells, as first shown at this Imstitube, and since widely confipmed11•z3.4 R.f: causes aingk-aelled organisms to become oriented in the electromagme;ic f eld, and'also affects structures inside fiving, cells. Appfia.don of r.f, fields to dividing cells im the gowing .ruat tip of the gat',lic plant, for iopicakplVe, va - ~ i<pon f~o~ --- inter- *t r~ t0"c~4~+~ivt ~: `Laepeadialg` ~On UP" ~~ v~e ~iiaal io~ of celL d'e~ri- ~ a Sre~t ~ ,slurJear: chromo- romall#iragpncata~, suad loss of genetic materiaL These. Juwchaages eventually result in death of the cell.. ImpliCaoip,ns of,; " type of' allular response to aeptnmt qithr:£ in onacies ~ at+e obyicxis. We are .~Id~irhins iat t6iu Io~itwt~spedfic frequencies which may inhibit reprodirtim, of malignant cells without affecting qoraaal cells. The r.f. effects we are studying are non4hermal:. Thermal' effects have been known for years. Appllyiing', this energy ul pulses is designed'' to reduce heat to a bi- ologically negligible level'. To make sure of' this point,, special' thermal controls are set up. Experiments to de, fine the range of temperature shocks in dividing cells of 0 phila have been publiushed.s Fundamental changes in the hereditary mechanism appear to result from treatment of germ cells withh r.f. Experiments with i the fruit fly, Drosophila, have yielded l both dominant and recessive visible mutations, as well as sex-lihked'recessive lethal mutations which destroy malle flies receiving, th,etm,6 Furthermore, r.f. induces "crossing over" in the germ cells of male Drosophila, a phenomenon occurri=lg, naturally only in the female fly. These genetic effects resemble those resulting from ap- plication of ionizing, radiation, which has tremendously greater energy levels. However, the dose of X rays necessam to produce the same amount' of crossing over in, the male as does r.f. also produces many other simul- taneous effects; r.f, does, not, . Treatment with r.f. and gamma radiation, either sequentially or simalltaneouslly, appears to have a syner- gistic effiect„ producing, more mutations than, d'o, such agents used! i¢idepend¢ntl~+, a phenomenon now being invest'~ ,atedl further because of its obvious interest as a potential combination therapy in malignancy. Research is being vigorously' pressed' to elucidate the processes controlllirsg, these phenomena and'' to ex- plore the range of genetic changes prodkiced at different frequencies. Tissue cultures of mammalian cells ('iin- chuiing mouse, hamster, opossum, and' man), using tiime-lapse cinematography, serve as additional materials for tlhde inWQsti,gation& Reapoasible' for'the cyrogenetsc uI>ECCS of this work is Doctor G:~ H. Miclaey., . Devekpffsewal Ge"ies Studies at the Institute on the deaelopmntal patterns in herediity aad grounit . by Doctor K. C Svndhi have re. sWned 11oorntly in '~ubliruioa of':pevew ~ ow1ytical'' and ~LP ~4JI~i~s Yi~# ~14r1r~~ SYsteais Im w.~t to ol" a' toetaa;' ~ding of' the ~iaa4.l Of the''.effects Of t:f,, experiments have re- cenr,ijr beea i. arr.ied out iq~ noo4ilogical systems by Doctor J. •X Hellrc end Iloor D. J. Willtiins. ~i awrfewe d'tuse ,of =pDlloids is markedly reduced bqrexpcvtc Wr.f. &ivaicydwst miaes. In terms of the energy Mqwiced~ ~oo ruhrce "charge underr current theory, r.f. falls short by an eaorm.ous factor.10 Further,, the length of waves: req;uirad! to produce the change' is quite specific and discrete, depend'ing, upon, certain physical' parameaers for which no lleciown physical theory appears to provide adequate explanation. This work in phyrsica aad~ physical chemistry may have sigoificanoe in, many 5ekb of scieave. It has given . added htipetus to our studies in biogeophysics. Becausee of the diversity of factors in bibgmophysicalt studies, and the great intellectual atud experimental rigor which they demandi a special Biogeophysics Advieory CoMmittee. has been set op comprising Dr, Sverre Petterssen, Pro~ fessoc of Meteorology and Lbairman of the Department, University of Chicago; Dr. Joseph~ Kaplan, Professor of Geophysics,, U.CL.A.; Dr. Colin Piteendrigh, Ptofessor' of Biology,, Princeton University; Dr., Walter Drr' Rob. erts,, Director of the U'niversity Corporation for Atmos- pheric Research, Boulder, CfllocadoG and Dr. Helmut Land'sberg, Director of the Office of Clicmatollogy,, U. S, Weather B'ureau: Increasing Resistance o f the RES to Diaease Research has been conducfled for several years at this' Institute on methods of' srimulating, the primary defen- sive system of the body, the redculloendothelfal system (RES ), to prevent disease due to bacteria, viruses,, and toXi.11 12, 3,14;19'. Recent studies have shown that a major increase in resistance to disease results from stimulation of the R&S : by lipids (a group of organic compcounds ~ related to fats andl oils ) and is intimately involved with thq individ'ual's immune' state. Under stimulation,, the RE.S' markedly increases phagocytosis,l's.1° but stimulation, of', phag&- 80690Q84'

cytosis al'®ne may have no effect oni survival of anitnalls challenged with pathogenic' organisms. With the lipids' under study here we find an increase in antibody forma- tion as well as increased efficacy of antibodies, as seen in passive immuniz'ation: Thus, stimulation of the RES significantly enhances resistance. Production of antibodies in rabbits has been in- creased 70-fold by lipids from shark livers ini conjunc- tion, with a conventional' immunization schedule. These studies are being conducted by Doctor J. P:. Ransom and' Doctor E. G. Bliznakov. Collection of livers from sharks' is carried out by Doctor J. H1H'eller' and! ML S. Heller, with the collaboration of Doctor E. Clark. Preparation and refining of the lipids from, the' livers is directed by Doctor V. Z. Pasternak. This research involves considerable colloid chem-, istry. Doctor D: J. Wilkins is developing colloids with control over size, charge' and surface groups. Two ofi these variables are heldlconstant while the thirdd is varied. This requires the synthesis of colloids of' predetermined characteristics through involved techniques of physical and' organi'c chemistry'. The' colloids, roughl'y ofl bacter- ial dimensions,, carry built-in electrical surface charges, with a fluorescent dye incorporated throughout their structure. The surface charge, applliedi as a"skiin"' off macromolecules, can be varied at will. Other studies involving colloids,, designed to de- veiop a' test of resistance in man, have produced unex- pected' data which may throw significant new light on liver function in transferring, certain colloids from the blood stream' into' the' intestine.'8 New As pects o f Immunity to Disease A system in many respects ideal for RES studies is the fertilized hen's egg, which at the outset is devoid of antibody-producing mecha'nism, In such a system wee have shown that resistance' to infection of embryonared eggs may be qualitatively modified by adding antibody and immunologically competent tissue (splleen ) from' an adult normal' or immunized chicken andi ani RES- stimulating agent, or combinations of these;, as judged by survival to challenge by an infectious agent (Sal- monella tyliliirrzurium ) which i's' lethal for eggs' in doses of as' low as one' bacteriall cell per egg..19,20 . Resistance to Cancer and the RES Instiuute' scientists are beginning an extensive new pro- gram of basic research into the possible role of RES' stimulants in increasing resistance to cancer. Preparation is under way for seca.ring, considerable quantities' off the lipid from shark livers which, provides major stimulation of the RES. This lipid& is used in studies of embryonated eggs and mammals to determine whether the stimulation of the' RES' conferred by the shark liver lipid against infectious diseases will also dis- tort the host-tumor equilibriurn ini favor of' the host. Doctor Ransom and Doctor Bliznakov are con- dilcting the initial wges of this new investigation, Microbial Interaction We are growing several types of microorganisms to- gether' in a continuous culture requiring elaborate ap- paratus to provide a constant excess of' nutrient coming into the culture and a, constant effluent ofl microbial waste products. Intriguing, in this work is' the fact that certain microorganisms inhibit the growth of others, by some'unknowni process.21•22 In recent studies by Doctor Ransom with this' system, a, normal yeast inhabitant ofl the human intestinal' tract markedly interfered' with the growth of certain pathogens causing intestinal disease. Preliminary experiments' have shown that a similar in- teraction occurs in mice. M New Studies on Proseins Dic. T:loydl H. Reyerson, is doing basic research on proteins at this Institute, using a new' techniqpe for studying their functions requiring the use of physics, physical chemistry,, and other sciences:23,241 His findings may help science to' understandi the' biological behavior of many different protein groups. RBFffitENc.BS To, TEKT 1. Further in.exieatioa iaoo radio Nteqoency e~aca whicfl appear to be acrive, on the RE8 in wholt-bodj. itradlation. f. H Hella and A: A: Tei:eir.,Pinto: RES'Bnllain, 4:10„ 1958.! . 2. A new phT-:cal method of' creating chromowmal' abertations. J. H. Heller and' A. A. Teiuira,Pinto. Nature; 1S3c905, 1959. 3. The behavior of' unicellular or iu an electromagnetic field. A. A. TeizeixaPinto, L. L Nejelslti,, r., ~L. Cvtlkr„ and J. H. HeUer. Experi- mental' Cell I Research, 201549, 1960: 4. Non-thermal' effecta of radio frequency in biolasicall syaoems. J. Hi, Heller and G. H. Mickey. Digest, International Conference on Medical Eleetronics, 152,1967. 5. Mitotic alteruiam in Drosophila resulting from temperature shocks. G. H'. Mickey. Bios, 33:58-73, 11962: 6. Electromagnet 5aciaty ofism .nd ts effect on the arg.nism G: HL Mickey. Journal of the Medical ithe Snur of Idew Yorh. 1963' (in ptea )'. 7~ Patterns of gene pleiovopy' in morphagenetic processes. S. C. Sandhi. Science., 137:5381 1962. ,8. The evolution of a pattern. IG C. Soodhi. Evotution, 16'c 186, 1962. 9. The dynamics of pattern formation. K., C. Saadhi and' J. Maynard Smith- Saientifie American; 1963 (in press). 10. Effects of radio frequency 6elda on the aen potential of  colloidal suspen- sioa J. H. Heller, D. J. Wilkins, J. F: Freeborn. Ntture ( Iandon ), 1963 (in press ) . 11. RETICULOENDOTHELIAL S1Ri1C"I1JRE AND: FUNCZ1oN: Ronald Press, New York City; 1960: J. H'. HeUeri Ed. 12. Mbrpholo~tc chao8es accompanying RES stimulation. M. ICojima.~, Annads of the New York Academy of Scienees, 88:196, 1960: ,113. The enhancement of' hetnolyaio, productioa in the rat by Zymosan. J• L. Cutler. Journal of Itnmunolog~, 84':416, 1960. 14. Nontoxic RES ximulamry lipids. J'. H'. Heller: Aunall of the New York Academy of' Sciences, 88! 1I16', 1960. 1'5'. Effect of' Zymosan an eryth'rophaga¢ytasi4. J. L. Cutler. Journal of Immun- alogy, 86173, 1961. ,16. Effect of a reticuloendotbelial stimulating agent ( resrim) on resistance of' mice. J P. Ransom, V. Z. P.sternale„J: H. Hbller. Juurnallof Bacteriology:,84:466, 1961 17, New advances in stimulation of the RES:, I H'. Hltler, J. P. RYnsam, V: Z. Puternak. Proceadingt of, Symposium, Centre National de 1.l Recherche Scientifique, Paris, June 20. 1962. 118. Rapid appeuance af' injected fat in the gut of' the rat D! l. Wilkins. Proctxdings af the, Society far Esperimentali Biology and Medicine. 1963 (in preat ) . 19. Action des agents stimulants du syst2me nhiculo-eadotBEliad sur, Ia rEsilnnce des embryoos de Poulets porteun d'une greffe dt rate adulte. Jl P. R.asam, E. G. Bliznakov, V. Z. Piaoernak et] H.. Heller. Compoes rendiu Aes 4Eances de Is SociEoE de Biologia; Tome CLVI, no. 6, p. 1022, 1962. ,220. Modiftication af: Salmonella typbimurium infection of embryottated eggs by anriserum;, adult splenic tissttr, and combinations of these .genn: E:, G: Bliz- nalCOv, J• P. RinsomandJ. H:. Heller. Proceedings af.f the Societyfar. Ex-.. perimental' Biology and Medicine, 112e367, 1963. 21. Interaction of continuously, fed cultures of Vibrio cholerae, enterococci andl tactobacilli. Ji P. Ransom, R. E. Ceder, and S. B. Formal. Bacteriolo8ical, Ptaceedings, 117, 1961. 22. Interaction of Vibrio cholerae„ Shige1L flezneri, enteracocci, and lacto- bacilli in continuously fed culmres: J. P. Ranwm, Rl A. Finkelitein,,R. E:, Ceder, awd' S. B. Formal. Proceedings of the Society for Experimental Bi+ ology and Medicine, 107i332, 1961. 23. The sorpaion of Hx0 and D20 vapon' by lyophitined' ~l4ctadobulin andl the deuterium exchange effect. Lloyd H'. Reyerson and' Wasyli S Hnojewyj, Journal of Physical Chemistry, 64i811-815L 1960. 24. Further studies on the sorption of'Hz0 and Dz0'vapors by lysozyme and the deuterium exchange effect. Wasyl', SJ Hnojenryj and Lloyd Hi Reyerson:, Journall of' Physical Chemistry. 65:1694, 1961. 80690085

I . NEW ENGLAND 1NSTITiJW FOR MEDICAL RESEARCH Grove Street, Ridgefield, Connedicurt; 438-65411 BOARD OF' TRUSTEES Lieutt Gen. Leslie R. Groves (ret), Darien, ConnL George C. Haas, Jr., Ptesidenti, Haas Financial Corporation, New York, N. Y.. Dr. John H. Heller, President, New England Institute for Medical Research, Ridgefiekl, Conn. Dr. Marjorie Knauth, Wilton; Conn. George M. MeCorkle,, Vice President, New American Library of Worldl Literature, New York, N. Y. Paul A. Peaslby, Vice Ptesident,, Fairfield County Trust Company, Statn6ord4 ConnL Edward L. Schulhe, Vice President, Galbreath-RufCm Corporation, New York, N. Y. Robert T. Tate,, Jr., CounselJ Esso Standard' Division, Humble OiJI& ReBining Company, New York, N. Y. OFFICERS Dr. John H. HeBer, Emexucive Director Robert T. Tate, Jr., Secretary William IL Hiatsoni Vice President G. W. Brown, Treasurer and' Administrator SCIENTIFIC A@VIISORY' BOARD Dr. Walter L Brown Dr. Clark Goodman Dr: Q'ierald, W. Johnson Physicist Vice Pltesid''ent. Assistant to Secretary of Defense Bell Laboratoriies Prengle,, Dunker & Crump, Inc. for Atomic Energy Dr. (harlea A. Doan Dr. Albert S, Gordon Dr. Joseph Kaplan Dean of the Medical School; Emer. Professor of Biology Ptofessor of Geophysics Ohio State University New York University U.C.LA. Dr: William Von E. Doering Dr: Robert J. Jeffries Dr. Leo Pospisil Director, Division of' Sciences President Associate Professor of' Anthropology Yale University Data Cnntroll Systems, Inc. Ya1e University ADVISORY ' COUNCIL CHAIRMAN: James L Turrentine, Assistant to the Chairman, Pitney.Bowes, Inc.,, Sramford,, Conm Charles D. Agnew Wilton, Conn. Hon. Prescott Bush Greenwich,, Conn. Tyler P. Cobb Manager Sales Operations. American Can Co. New York,, N:. Y. Vice-Adm. George F. Hussey, Jr. ('Ret. ) Norwalk, Conn. John B. Jessup Attorney at-Law New York, N. Y. E: G. Bliznakov, 1W1.D: * E: Clark PhD:. *D: Fogel, M.D:. S. C. Harland, Ph.D. J. H. Heller, II?I'.Di . ' Reswairch Associate Thomas R. Jones Vice Chairman Schlumberger, Ltd. Murray Hill, N. J. Harold D. Lasswell Professor of' Law Yale University Francis D. Martin Ridgefield, Conn. Karl S. Nash President,, Acorn Press Ridgefield, Conn. Harvey Picker President Picker X-Ray Corporation White Plains, N. Y. Jlohn, L Senior, Jr. Ridgefield,, Conn. E. P. Snyder, Jr. Partner Moore & Munger. New York,, Ni Y. George A. Nelson, Jr. Ray?rnond J1 Wean Vice Ptesident President Andrews, Nelson, Whitehead, Inc. Wean Engineering CoL Inc. New York, N. Y. Warren, Ohio DOCTORATE STAFF *I'. IConstanrinu,lwt.D. W. R. Pistey, Ph.D. John i Lee, Ph.D. G. H. Mickey, Ph.D'. * J: M : O'Brien, hdlD: V. Z Pasternak,, Ph.D: *A. Perks, Ph.D': J. P. Ransom, PkD.. D1byd! H. Reyerson, Ph.D. *S: Soloway, Ph.D.. D: J. Willcins,, PhLD! I I