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Mr. J. L. Bacon Page four February 21, 1980 tional" slow-acting viruses. Their papers,referenced by the National Library of Medicine, indicate that they have NOrI' worked, as might be read from the mernoran- dum of October 1979, on Kuru and/or Creutzfeldt-Jakob disease, but they have worked on scrapie, etc. among the "unconventional " agents, and/or Visna, etc. as far as "conventional " slow viruses are concerned (please refer to table above). All of these researchers have also worked on other virus proble.m and . on other topics not related to viruses. I have looked at the rather prolific work of all these investigators,, published during approximately the last ten years. I have, however, paid most detailed attention to the papers of the potential senior investigator, Dr. R. N. PRUSINM (from 1942). His work has been examined since his earliest iden- tified paper, published in 1965 through his latest publication on record at the National Library of Medicine, published late in 1978. Astonishingly - and same•- what pertuitingly - Dr. PRUSINM does not seem to have published a single paper in 1979 or in 1980, even though he has published prolifically, i.e. several papers per year - through 1978. This has been confirmed by a computer search of the National Library of Medicine holdings, as well as by a computerized search of another data bank (Institute of Scientific Information, Philadelphia, PA), as well as by a conventional library search. By and large it can be said that the quality of the work of that group can be assessed to be at least average, or very likely even above average, but not outstanding or path-breaking, and certainly not "off the beaten path". T":ciM pa.pers were and are published in very good and, at times, in the most prestigious journals; this means that,their work has successfully passed the peer review of other high caliber scientists. There are a great many teams, not only in the U.S. but also in Europe, etc., Who publish worthwhile research on "unconventional" slow-acting virus-like agents. I fully agree with Dr. Seitz and Dr. Shannon that this is a field "extra-

M13t-OFFICT MI1SORaNTLTM DRAFT .- q.,,,n,.. February 21, 1980 Mr. J. L. Bacon RE: ASSESS;~EN'P OF "UNIVFELSITY OF CALIFORNIA, SAN FRANCISCO - SLOW VIRUS RESEARCH". Prof. S. B. PRUSINER and associates SU1MARY The information provided to us is insufficient to make a reasoned assess- ment as to whether or not the San Francisco slow virus research group deserves our financial support. The main reason is that, while we have reasonably adequate dataon the past performance of the SF group and their area of research in general, we do not have the slightest information as to the specifics or even the general thrust of their plans for future research. Our data - in an area of research com- pletely new to us - had to be compiled, read and evaluated in less than two days. Our examination was therefore fai'rly cursory. But we assess the quality of the work of that group to be at least average, or very likely above avera€;e, but not outstanding or path-breaking, and certainly not "off the beaten path". It is also a type of research which, in my judgment, should not have too many difficulties in securing funding fran N.I.H. and/or other sources. The request should therefore be examined with a great deal of care, after a cornplete research proposal has been submitted. 119DRAN)UU 1.) Perspectives of "slow virus research". The term "slow virus research" is somvhat of a misnomer, since it suggests that one basic type of agent is at work, however, in reality it"embraces a number of diverse agents, only united by the chance that they produce diseases

Mr. J. L. Bacon Page three February 21, 1980 The following table identifies the central nervous system diseases which are allegedly associated with slow viruses or slow virus-like agents (as defined by Groups 1. and 2. above.) Slow virus diseases of the central vervous system in animals and man Host Infectious agents Unconventional agents Conventional viruses Animals Scrapie Visna Transmissible mink encephalo- Canine distemper demyelinating ence- pathy phalomyelitis Men Kuru Subacute sclerosing panencephalitis (SSPE) Creutzfeldt-Jakob disease Progressive rubella panencephalitis (PRP) Progressive multifocal leukoencepha-• lopathy (PML) Authors: V. Ter Meulen, University of Wt.trzburg/Germany, and W. W. Hall, Rockefeller University, New York, N.Y. Title: SUJ1V VIRUS INFECTIONS OF TY.E NERVOUS SYS'MI: VIROLfJGICAL IM7[JPZOIAGICAL AND PATI1OGFNLT I C COPdS IDERAT IONS Journal Gen. Virology, 41: 1-25 (especially page 2) (October 1978) To repeat, the work which, in my judgnent, the SF group wants to be funded for, refers to the "unconventional agents" in the first column of the above table. 2.) Comments on the S.F. Researchers I have assessed the work of the researchers identified by name in the rrxinorandum prepared by Drs. Schmid and Prusiner of the SI~' group in October 1979,v.tich is attached to the letters by Fred Seitz to Coiin Stokes of February 13 and/or ~ January 21, 1980, which were also sent to you and Jack. As indicated in the nxwro-- randum, several of the researchers have studied both "unconventional" and "conven- N v i 4n

Mr. J. L. Bacon Page five February 21, 1980 or: inary in interest, opportunity, and importance", but it is, in rrty jud~ent, an area where obtaining funding from ;t.I.H. and non-goveriunental sources should not be overly difficult. Also, I am personally "prejudiced" in favor of funding fundamental research «hich is "off the beaten path" - though in the case of the SF group the "beaten path" is only about twenty to twentyfive years old - even if there is a risk of not yielding data worth publishing in a major scholarly journal. I am also somewhat apprehensive, because the background of all of these researchers - though generally excellent - is mostly - though not exclusively - Aveighted towards the medical side of the needed biomedical sciences. It is therefore possible that the SF group lacks sufficient background and expertise in needed very sophisticated biophysical and biochemical disciplines. With reference to the simultaneous funding of Dr. PRUSINER from the Howard Hughes biediu Foundation, I share the apprehension expressed in Drs. Seitz and Shannon's comnents, but I understand the footnote in Dr. Seitz's letter of February 13 to mean that this is no longer a problem. 3.) Background for Assessments These evaluations are based to some extent on reading a series of revioc with e7rphasis on their alleged effects on the central nervous system. paper in the general areas of slow viruses and virus-like agents / Five of these review articles are attached. The article which is nbst beneficial for your reading is the one by NIIMISAN from the (loose-leaf) textbook on "Medicine", published in 1979, and continuously being updated„by the Scientific American. Also of ~pe- cial interest - though not discussed above - is the-editorial by L.GROSS from the August 23, 1979 issue of the New England Journal of Medicine, which specu- lates on the potential extension of the research on diseases of the nervous system, allegedly caused by "unconventional" virus-like agents, into the field of cancer. ~ 0 N v ~ I personally would much prefer if the SF group or another group consi- ~, ~ ~ N

Mr. J. L. Bacon Page two February 21, 1980 with excessively long incubation periods "(R.N.Sutton, Postgraduate Medical Journal, 55: 143-9, February 1979) Depending on definition, one can distinguish three or two large groups.of such "diverse agents". GROUP 1.) "Unconventional" agents, the physico-chemical makeup of which is almost totally unknown. While they have several similarities to "conventional" viruses, they may in the future turn out to be not viruses but an entirely novel class of biological entities. GROUP 2.) "Regular" RNA viruses, but which are distinguished from "con- ventional" viruses mainly by the fact that they have alilrays excessively long incubation periods. GROUP 3.) "Norma.l" "conventional" viruses which usually have "regular" incubation periods, but which under certain circumstances, are modified and then have similarly long incubation periods, as the agents described under Group 1. and Group 2. above. (Some investigators prefer to consider Groups 2. and 3. together, or disregard Group 3. alltogether, when discussing "slow" viruses.) To my understanding, the work of the SF group for which they wduld like support from our 'biormdical research program', deals with the "unconventional" our knowledge agents. As far as concrete biomedical data are concerned,/ is, at present, by and large, limited to the alleged manifestations of these agents in the central nervous system of man and animals. Their involvement - if any - in other organs or diseases is speculative. However, the greatest importance of the slow virus research may well lay in its possible extension to other diseases of unkno%I.m etiologies, such as multiple sclerosis, Parkinson's disease, lupus erythematosus, chronic arthritis, cancers (see also below), juvenile diabetes, etc.

Mr. J. L. Bacon Page six February 21, 1980 dered for funding by RJR, would explore such extensions of findings with "unconventional" agents, to cancers and/or to areas other than the central nervous system. However, assessment of the work by the SF group is mainly based on the attached researchers' profiles. Each profile includes a biography of the inves- tigator, and a bibliography of his or her publications for approximately the last ten years. Regarding the biographies, it should be noted that most of these investigators are relatively young, and none of them seer.is to have received to date any special awards or distinctions, other than regular academic promotions. (No biographic information is available on Madame BRAHIC, except that she was a researchers in France before coming to the U.S., approximately in 1976 or 1977.) (I have also assembled a similar profile on Dr. R.SM4ID because he is indicated as a co-author together with Dr. PRUSINER in the above mentioned four-page write- tp by the SF group about its work, dated October 1979.) I also have - at least cursorily - considered other sources not mentioned here. Because of lack of time, this memorandum could not be propeFly edited and should, therefore, be considered a draft. FGC/ks cc: H.C.R. M.H.C. Attachments AE ~ Cw~`~