[This letter was submitted to Science by W. D. Hamilton, 27 January 1994. A slightly revised version was later published as an appendix in Julian Cribb, The White Death (Sydney: Angus and Robertson, 1996), pp. 254-257.]

The headline "Rolling Stone rolls over for Koprowski" (Random Samples, 26 November) is right for the "clarification" that Rolling Stone published but your piece that follows oversimplifies. A reader might gather (as also from your earlier column on the Wistar Institute committee's report {30 October 1992, p738}), that the idea that the pioneer polio vaccination campaign in Central Africa in the late 50s could have started the AIDS pandemic is now thoroughly dismissed.

This is far from being the case. The "clarification" that Rolling Stone published on 9 December 1993 hardly says more than was obvious to most readers already -- no objective to defame. The original article was good science journalism. It was well researched and was attentive to alternatives: I was astonished that Koprowski sued. After a re-reading I still cannot see what, apart from a very slight geographical error which concerns only the two sides of one valley, plus a retracted report (1) that Curtis might have noticed, Koprowski considers unfactual, unreasonable, or unduly ad hominem in the matters described. Tom Curtis, the author, was airing a scientific theory and had as much evidence as is usual initially. The theory he wrote about admittedly has snags, but so does any. It is easy to make a longer list of plain errors from Koprowski's ("As a scientist ...") brief rebuttal (2). {SEE APPENDIX-NOT for publication}.

Regarding snags to the Curtis theory, let us admit first, for example, that the evidence is for a precursor SIV from chimpanzees: how would that have arrived in an attenuated polio virus vaccine raised in cercopithecine tissues? Second, if reaching such cultures, how could the SIV multiply in a monolayer kidney cell medium that did not include the virus's preferred cells, CD4 lymphocytes? Third, even if the culture could have been based by error upon tissue of a chimpanzee harbouring an SIV, must not absence of the favoured cell type still exclude the virus?* Fourth, why is the geographic fit of AIDS in Africa to the polio campaign of the region not matched by a corresponding fit in Poland where a parallel early campaign was applied and no early AIDS appeared (2)? Fifth, how explain a Manchester seaman dying of AIDS too soon to have been infected from the vaccine (3)? And so on.

Similar snags, however, can be produced to all the other theories. Yet clearly the AIDS virus came to Homo from some other species and did so via unusual events just as does any parasite moving to a new host. All the above snags can be answered in ways that, while not yet dismissing them, at the very least suggest further work. Thus SlVs are known to exist as deeply divergent genotypes within single wild primate populations (4) and this implies that SlVs much more similar to HIV-1 may yet be found in the monkey species [but which exactly? -- no one seems to know (2, 5)] that were used for the vaccines. Neither this idea expressed by Curtis in his article nor that of an unusually rapid evolution as the virus begins cycling in a new species, is at all unreasonable. Assisting pathogen "passage" several or many times through a new host in which it is to be cultured, is standard and is nothing more than the experimenter inducing rapid evolution, a rapidity potentially greater in retroviruses through their diploidy and recombination. Turning to the second snag, contamination of tissue cultures with retroviruses is common even in the best endowed institutions (6) and Koprowski's team was regularly dissecting chimpanzees in the conditions of a remote Congo laboratory (7,8) for purposes connected with polio. Third, lymphocytes are not completely absent from kidney tissue cultures (9,10) and there are many other cell types which HIV-1 and its simian cousins can infect with or without contaminant viruses aiding their entry. The paper (9) on which the Wistar Committee relied in stating HIV-1 could not survive in the cultures did not consider the issue of co-infection and was weak in several regards. Even its main conclusion was unclear as the SIV may at the end have been increasing. If HIV-1 can be grown at least with co-viral assistance in non-immune-system tissues cultured from organisms as distant as mink and mouse, as has been done (11), why should a simian precursor of HIV not gain entry and multiplication in pre-infected, non-lymphocyte tissues of an unusual host primate, or be pseudotyped onward with help of the same or other co-infecting virus into the tissues of yet another host, Homo? Indeed might it not increase virulence to become more HIV-like during such a passage, as has also been shown (12). Fourth, the Polish polio campaign was on a very small scale (one hundredth) compared to the Congo trials, did not use intra-oral spray, and unlike the African trial (13) excluded neonates as subjects for inoculation (14), all points which severely weaken the comparison. Fifth, it is not true as Koprowski has stated that he could not be a secondary case arising from a contact from Africa. He had visited Africa and the dates although unlikely to mesh are not impossible.

It is not my object here to say that these ways around the snags I have mentioned amount to any great joint likelihood, still less to say that the theory Curtis reported is the most likely. My object is simply to emphasise that every theory has snags and ways round them, and that the proper course of Science is to allow all theories to be discussed so that their critical points can be focused and tested. It is certainly not the way to use lawsuits to terrorise individuals and journals that try to promote discussion. Being burned alive as a heretic is admittedly worse than facing financial ruin as a heretic, but except for the threat being different we have seen this mode before and have also seen, last year, its belated and shame-faced finale in the Vatican's apology to Bruno and Galileo. Are we starting this all over again with a Medical Establishment now in the robes of the universal Roman Church? Apart from shame in the method, the overcrowding of present humanity plus its fluid mixing means that in respect of future human epidemics, failure to heed lessons before launching new public health campaigns has a potential to result in hundreds of millions of deaths. Nor is it just potential if the AlDS-polio contention turns out to be right and the above rough figure is certainly no overestimate. Mistakes in this field are much more directly dangerous for all of us, and dangerous even within our lifetimes, than was the failure to face up to the heliocentric theory of the universe.

A circumstantial case that the precursor virus of HIV-1 (not HIV-2) might have transferred to humans during the polio vaccination campaign in the Congo seems to have stirred action in a half dozen or so scattered people. Others followed them, Curtis, for example, writing for Rolling Stone in support of originator Elswood. Concerning an earlier, independent, more detailed, yet still closely parallel version due to Louis Pascal (8), the editor of the Journal of Medical Ethics wrote recently that it was "important and thoroughly argued" and deserved to be "taken seriously by workers in the AIDS field" (15). Before I read the Rolling Stone article I already had been strongly persuaded by Pascal's account that there was a serious case to investigate. I was shocked by his evidence of outright and never explained resistance to his idea from medical scientists and journals. Koprowski is clearly far from alone in feeling the idea should not to be aired. Yet in Pascal's account as in Curtis's I detected nothing that seemed exaggerated towards defaming Koprowski, instead only a wish to outline a possible huge tragedy that might have arisen from a noble venture, a great good and a great bad tangled together. Above all he had delineated a tragedy which, if real, should at all costs be allowed to imprint its lesson on future policy. Proponents of the idea mentioned so far are none of them scientists. Two who yet again published it independently, Lecatsas and Alexander, are professors of virology and microbiology respectively (16). An idea occurring to scattered, diverse, well-informed people, that many others subsequently have acknowledged to be worthy of study, and that has been noticed in Research in Virology (17), cannot be considered frivolous or devoid of evidence. It did not deserve a lawsuit.

A strange feature of the case is that a step towards a refutation of the idea is readily available. A sample of a vaccine stated as possibly relevant to the Congo campaign have been located at the Wistar Institute and yet so far no test has been reported nor any sample released for testing (10). If provenly untampered samples of the questionable batch of vaccine are tested and convincingly found free of SlV/HIV-type viruses, this would go far towards dismissing the theory. Testing for and even sequencing a retrovirus if present is relatively easy but contriving an acceptable setting and protocol may be less so and perhaps that is the difficulty. Nevertheless that almost two years after the original Curtis and Pascal articles came out, and twenty months after discovery of the stored samples, nothing should be even in motion towards testing them seems extraordinary.

After six months of deliberation a panel convened by the Wistar Institute to examine the AlDS-Polio theory produced a strongly dismissive report. This ended, however, with the oddly contrasted recommendation that current methods of raising vaccine viruses in non-human primate tissues should be superseded as soon as possible. Several items in the report seemed weak, some being answerable on the lines I have touched on above. Oddest of all the report gave only lukewarm support for testing just one of the many vaccine or seed samples related to polio that are at the Wistar Institute. These could even, one would think, have been tested within the six months of the committee's term. Curtis has summarised the outcome as like a jury bringing a verdict of not guilty when an obvious key witness is still waiting in the courtroom to be heard.

The Wistar panel's final suggestion that the technique of raising attenuated viruses for vaccines needed to be changed appeared to admit overstatement elsewhere. Similarly thirty years ago, four years after the Congo campaign began, Hilary Koprowski, then as now (2) believing that the techniques he had used were danger free, became a pioneer spokesman for an identical view on the undesirability of non-human primate tissue culture for virus vaccines.

To conclude, cercopithecine tissue culture is still being used and at the same time other techniques that might also facilitate species jumps by pathogens such as organ transplants from non-human primates into humans are increasing fast. These various medical techniques may be very dangerous for human future, indeed they could conceivably deny humans having a future. Scientists should listen to and investigate with due care common-sense suggestions and warnings arriving from outside their ranks; they should not endeavour to suppress them (18). In the face of overbearing professional mystique, disregard, and now even litigation, the public is justified in its growing disillusion with science and also in some of its deepest fears.

1911 words

W. D. Hamilton
Royal Society Research Professor
Department of Zoology
Oxford University
South Parks Road Oxford OX1 3PS
England

* Not for publication: I am aware of the recent exchange in Lancet about negative testing of some more vaccines and the issue of trypsinization. However (a) the new findings were not available at the time of the Koprowski lawsuit, (b) they were challenged, and (c) the spirit of the exchange shows that some in medical circles are taking the Curtis theory seriously, in keeping with my letter's theme that seriousness is deserved.

REFERENCES AND NOTES

1. R. Biggar Lancet 1985 ii 808 (1985).

2. H. Koprowski, H. Science 257, 1026 (1992).

3. G. A. Corbitt et al., Lancet 1959 ii, 51 (1959).

4. Gao, F et al. Nature 358, 495-499 (1992); Li, Y. et al., J. Virol. 63, 1800 (1989); Johnson PR et al., J. Virol. 64, 1086 (1990).

5. H. Koprowski, J. Am. Med. Assoc. 178, 1151 (1961); T. Curtis, Rolling Stone, no. 626 (19 March 1992).

6. C. Mulder, Nature 331, 562, (1988); S. Wain-Hobson and G. Myers Nature, 1990. 347, 18 (1990); B. Culliton Nature 351, 267 (1991).

7. G. Courtois, et al., Brit. Med. J. ii, 187 (1958).

8. L. Pascal, Univ. of Wollongong Sci. Techn. Anal. Res. Prog., Working Papers 9, 5 (1991).

9. Y. Ohta et al., AIDS, 1989. 3, 183 (1989).

10. C. C. Basilico et al., Report from the AlDS/Poliovirus Advisory Committee, Wistar Institute of Anatomy and Biology (1992).

11. B. Chesebro, et al., J. Virol. 1991. 65, 5782(1991); P. Lusso, et al., Science 247, 848 (1990).

12. N. Rothwell Understanding Genetics New York: Wiley-Liss (1993).

13. A. Lebrun et al. Bull WHO 22, 203 (1960).

14. F. Przesmycki et al. Bull WHO 26, 733 (1962).

15. R. Gillon J. Med. Ethics 18, 3 (1992).

16. G. Lecatsas and J.J. Alexander South Afr. med. J., 76, 451 (1989).

17. B. Elswood and R. Stricker Res. Virol.144, 175 (1993).

18. B. Martin BioScience 43, 624 (1993).

Appendix

Errors in ref. (2):

1. The Ruzizi river is the boundary between the region of Burundi where the Koprowski team conducted its first large scale vaccination campaign, and the Kivu District of what is now Zaire. Curtis may have been slightly inaccurate but it is only a matter of the two sides of a river and it is certainly unfair to call him "completely wrong". On the scale of a map of Africa or even of Zaire and in a comparison of the map of the polio campaigns with the map of the distribution of AIDS the distinction makes little difference.

2. The first AIDS case listed in the source Koprowski cites was in Kinshasa where a campaign using the suspect CHAT vaccine had been applied (13). The two following were in Burundi where the first campaign was mounted (2). All three cases must be described as close to where vaccine was applied, contrary to Koprowski's implication.

3. No possible two points relevant to the discussion in Zaire plus Ruanda/Burundi are "thousands of kilometres" apart (i.e. all are <2000, while the absolute greatest distance attainable in the three countries together, about 2300 NW to SE, involves points completely irrelevant). Koprowski's claims on distances are wrong and careless.

4. The Manchester sailor's truly AlDS-like symptoms were not present "throughout 1958" but began in December 1958 (3). A quarter of a million Africans had been vaccinated by April 1958. It is therefore an error to say that the sailor had symptoms of AIDS before the polio campaign began unless Koprowski claims gingivitis and eczema confirm AIDS. It is more likely on anyone's theory these had been predisposing factors to infection. The sailor had visited Tangier. The time is short and he would have to have been a rapidly developing case, but he is not an impossible secondary case to follow from the African campaigns, as Koprowski implies.

5. Rhesus monkeys occur in India but not in the Philippines. If Koprowski knows of a naturalised or even captive population in the Philippines whence Rhesus were "captured" he should give details.

6. Koprowski's statements about the sources of his monkey's have varied (2,5) His paper in ref. (5) (J. Am. Med. Assoc. 178, 1151 (1961) gives both India and the Philippines as source and hence does not support (2).

7. Koprowski might have a basis for saying SlV-infected monkeys have few SIV infected cells in their kidneys but there is no basis from either of his given references for saying that they have none (see critique in ref. 8, Appendix).

8. Koprowski claims that the contaminating virus that Sabin claimed to find twice in Koprowski's material was in a seed lot for vaccine; but Sabin himself says he found it in vaccine that was used in the Belgian Congo (BMJ, 14 March 1959, 663-80) and in Poland (First International Conference on Live Poliovirus Vaccines, 577), and these claims were never contested on grounds of Sabin's mention of vaccine by Koprowski. Perhaps there are distinctions here that I do not understand but as they stand the statements conflict.

9. Curtis's claim was circumstantial evidence pointing to just one batch of vaccine as the possible source of AIDS. This batch was only given to about 3000 children in Poland and not to nationals of any of the other countries mentioned. Koprowski's large numbers of recipients with apparently no ill effects in Poland, Switzerland and Croatia are therefore irrelevant to Curtis's argument as he should be the first to know.

10. Koprowski's statement that "Again there was no doubt about the safety of the vaccine (given to 76,000 children in Leopoldville) because there were no untoward reactions that could be attribute to an extraneous agent" may be treated with some sympathy but is again irrelevant when the extraneous agent under discussion is expected to manifest on the time scale of the AIDS virus.

11. There was very careless editing and/or proof reading affecting almost the entire referencing of the paper. (This was however corrected three issues of Science later.)

12. Other matters are touched on in my letter. On one other yet, the adverse 'low' frequencies of AIDS Koprowski claims in the primary vaccination areas compared to higher frequencies in towns is too complex to take up in detail here and it must suffice to say that Koprowski appears to misunderstand that (a) the rates he mentions are not low by any standards in the world other than those of certain African towns, (b) Curtis did not suggest any but a very few, probably specially susceptible, recipients of the questioned vaccine were catching the precursor SIV, and (c) his thesis in no way denies probability that after the start, the well known pattern for venereal disease with prominent roles for prostitutes, travellers and towns, will emerge.