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Utdivl:IC`;1TY OF' C71L11'C)iMA, f;AN F1Z11NCI;;CO SLOW V.l RUS TU:M:?+Y.C13 .Although medicall science has made considerable progres . over the last century in deI.ineating the causes of many diseases and defining effective treatlnont regimens, the etiologies of numerous serious diseaszs af f] i ct.i ng hrun:_IrIs 1-cIi:~a i.n unknown. Z9ie causes of many cancers, arteri.o- sclcirotic ci-irdiovascular disease, schizophrenia, diabetes, rheuma.toid art_hri t_i s ar,d awide variety of neurological disorders including multiple scleros5.s, senile dementia, amyot.ropic lateral sclerosis and Parkinson's disease continuee to be enigmas. Despite considerable efforts using a variety of di sciha:,nes, including ep:idemio].ogy, genetics, virology, biocherni.stry and experimental medicine, the causes of these diseases remain obscure. One area of investigation which may offer new insights int:o-the --et.iology of tliese human disorders is that of slow virus research. Slow vi ruses have come under study only recently, for this new . ...field off i nvestigata.on was first conceptua].ized only ?_S years ago by an - . . . Zcel andic vet eri.narian. About that time the first slow virus di sease of man was discovered in •t:he eastern highlands of New Guinea. The discovery of this diesase and its recognition by Western medicine, under the guidance of Dr. Carleton Ga:jdusek, eventually led to the demonstration that kuru ' -was caused by an u.nusual slow viral-like'agent. For.his work on this disease, Dr. Gajdusek was recently awarded the Nobel -prize in medicine. From these studies and those of others, it is now apparent that slow viruses can infect. humans and then remain quiescent: for periods as long as three . .~. decades. After the: e prolonged incubation periods, a short period of

~Lc)w 1•12u5 i~_'.SCZIZC"1 : clir;ical i11c~c:curs, charz,ct.eri.st.icall.y leading to death. A se__cond di se. sc 1 ikc, }cs:!u is iound t.}uoughout t.hc• world, thi s dii:ease i.s named .after two c;c•rman neuropathologi.sts, Creutzfeldt and Jakob. The disease is also cnur,ed by an unusual vi.ral.-l.ike agent and incubation periods rZ,ngi ng f rorn two t o t.1-ri rty years have been documented. }~~x i,,c,rry yc-t;rs, Creutzfc:ldt°.7akob disease (CJD) was classified as a degenerMive c.:isease of unknown etiology occurring in older individuals. .The avcrage age of onset is in the sixth decade of life and neither the clinica] symptonL-, nor the neuropathology gave any, clue to an infectious or tranF.mi!aablc.! etiology. afie discovery of an unusual viral-like agent as the cause of CJD strongly suggests that other degenerative diseases wi11 also be fotuid to be caused by slow viruses. In many respects, CJD is sitnia.~~r to the more common preseni.le and senile dementias of the - .Alzheiux:r type. ~ secx>nd ..gi_oup of slow virus diseases caused by more conventional ~ -viruses include progressive leucoencephalopathy (PlII..) arnd subacute, scierosing pa.nencephalit-.i.s (SSPE). The slow viruses of PML destroy the nervous system of patients with conrpromised immunological. defenses. Patients with cancer, as well as inununos.uppression after renal transplantation can be afflicted by this disorder... SSPE is a. devastating disease of children caused by a variant of mc:a.sles virus. i3c:cause the discovery of slow virus diseases has had such an immense ,~~.~, _~._.~~.._...~.~_._.......~. . ..,.._ .__._..._...,..,_...,..,r.....~...,......._.......-.-----~•--o..........,._..,.........,.._..r----- ---.~ impact on ourr unc3erstanding off human diseases, considerable effort at UCSF is now being devoted to research in this area. Eight laboratories under It ,

S]C~~+ ~'lIU.`. lcLSC'ar"C'h I',,yc 3 ihe direction of 'University of California faculty memtiers are actively invc~,tig,xtiu~ r:_rrt i3I>s~ccts of ci_.ease_> cau;e-d by sJow_vi.rus>es. Dr. Stanley F'rusiner, A~:si:-.tant. I'rofess.or of Neurology, Dr. J. Richard Baringer, l1rofes sor of 2:euoaogy and Pathology, Dr- Daniel Stites, Associate Professor of I.aboratory Medi.ci.ne and Idedi cine, and Dr. Ma.chel l.e Sr.ahi c, hssi stant I'rofc•_ssor of 1:edicine, are all engziyed in studies on the unusual vi rzrl-1 i k e e agents wha.ch cause l:uru and 'CJD. Dr._Kenneth Johnson, Professor of Neurology -ind 3'at.ho]ogy, l>r.M A._hley }_3aase., Associate Yzofessor of Medicine and Microbiology, as well as Drs. I:<<,ringer and lsrah9_c are actively studying conventiona]. ,"'',,.,. . --- ......_.._._ . vi.ruses which cause slow oz lat.ent. infections. Several -of these investigators have already gained worldwide recognition for their studies. Currentl.y, techniques involving macromolecular purification, recombinant DNA technology, vi:ral. isolation, nucl.e-ic acid hybridization, electron -3nicroscopy, radioi-mnunoassay procedures, cell culture methods and ]aboratory .ani_mal rodels off d:isease are al.l. being employed to learn more about -slow viruses. The extraordinary elusiveness of slow viruses demand multidisciplinary approaches over prolonged periods of t:.i.me. For example, studies on the kuru and CJD vzr..al--like agents depend on bioassays in animals with incubation periods ranging from many months to several yeaxs. The unusually slow time frame presents a variety of difficulties not:.associated with more conventional biomedical research programs. Ille nx>st. exciting and challenging aspects of research on slow viruses lie ahead. 1t is likely that slow viruses will be shown to play an important. causative rol.e in many human illnesses. Z'hose human disorders where epidemiological studies have impl.icat.ed a transmis_sible agent, but none ___.__...~ -- -_._. _ _ . . .. . ._ -- - . . . .. . .. ~._. _ ,_,.-_..._.. _. _ ~. .. _ . . i

: IoL+' k17.7u s }U"'5caI"C}h Page 4 has :>een fc>>.:nc3 n-c'. i).-Irticularly noocd candidat:rs for having a slow virus c'.tiolocry. [>f tlle. disorders recorded above multiple sclerosis, juvenile (3iabetes, as well as the presenile and seni_le dementias, are now highly ; ur:i~ect of t)ei ng cau!--ed by slow vi.ruses. i I,vrr:-;t.i g,.,tors at UCSF worki ng in t}Ii s excit ing nc!w area al ready have forrned multiple cooperata.ve projects and. are anxious to paol tlreir intellectual and material resourc:es for a more concerted .rescarch effort. Wnat they need are funds to acquire urgently neec3ed equipment: for conurr,n use and salary support for young i.nvestigat:ors to work with them. 10/26/79