COMMENTARY CERTAINTIES THAT DEFY REALITY: FROM INTERLEUKIN TO TRANSFER FACTOR By Dimitri Viza M.D. In the post-September-11th world, it has become obvious that beliefs are often stronger than facts, that religion, politics, and economics are potentially cauldrons of conviction conflicts leading to disaster, and that experts too often fail to assess the present correctly, let alone foresee the future. Science, in theory, stands outside this contemptible scene of human stupidity; its credos are based on facts that shouldn't be dismissed without testing.  However, often certainties unwarranted by facts and difficult to unroot emerge. Following common sense, it is believed that in order to be efficacious, drug prescriptions should favour high dosage, and the more a disease is considered life threatening, the easier the implicit pharmacological risk is accepted.  This is not the belief of some parochial physician, but the subliminal conviction of enlightened medical authorities.  From the prescription of antibiotics to new immunoactive molecules, the tendency is the same: more rather than less, - possibly a reflection of our social values.  And one may wager that the pharmaceutical industry is no stranger to this state of affairs.  The use of interleukin-2 (IL2) in cancer patients may be an illustration. IL2 is a potent cytokine.  Its low-dose intra-tumour injection to combat cancer was first proposed by Pizza in 19841. One year later, Rosenberg, ignoring the previous publication, proposed systemic, intra-venous administration of high amounts for the same purpose 2.  In both instances, the results were promising, but the side effects of Rosenberg's protocol extremely severe. Although several publications3 have shown since 1984 that it is possible to reduce the amount of the drug without decreasing its efficacy, for the past 18 years, clinicians have clung to the high-dosage protocol, paying little attention to the alternative quasi-homeopathic amounts proposed by other scientists and, for that matter, to the suffering of patients.  Following the framework of modern thinking that more is better than less, they have forgotten one of the corner stones of biology, namely: catalytic processes require infinitesimal amounts of the catalyst to perform complex and sizeable reactions.  Hence, immunological interplay being part of life's biochemistry, cytokine administration should never have been confused with the massive daily protein intake necessary to satisfy energetic requirements, and even less with chemotherapy, particularly since it was established that 2000-5000 U of IL2 trigger a remarkable cascade of immunological changes a few minutes after injection3d.  Nonetheless, nearly 20 years after the first publication, nobody bothered to thoroughly investigate one of its most important claims, much to the satisfaction of the IL2 manufacturers.  Indeed, the average standard treatment uses more than 500x106 U for a 3-month period vs. less than 10,000 U for the low-dose protocol, i.e. 50,000 times less! A recent paper by Pizza's team4, using low-dose IL2 administration, confirmed the promise of the 1984 results.  In 122 metastatic-renal-cell-carcinoma patients, the survival was 3.5 times higher compared to that of historical controls, and without side effects, whereas, in other "recent studies, grade 3 and 4 toxicity has been observed in a substantial number of patients and 5.2-9.4% of patients died during the treatment periods, or within a month following the treatment, from causes unrelated to renal-cell carcinoma" 5. One may but regret that in spite of numerous reports on the effectiveness of low-IL2-dosage, thousands of patients have died or suffered severe side effects because of adherence to a dogma, that of the high dosage. Another aspect of the Italian publication is no less illustrative of the use of certainty as a shield against the unknown or the old-fashioned.  For in medicine too, fashion is present and discourages the utilization of drugs of the past, especially if they can be replaced by more expensive, modern ones. In order to boost their patients' immune system, the Italian team also used infinitesimal amounts of transfer factor (TF), a cytokine considered "medieval medicine" by certain immunologists today because its structure has been only partially unravelled6, and the mechanism of its biological properties Ð- apparently contradicting established dogmas - remains unexplained.  And yet, elementary logic tells us that ignorance of the chemical structure of a compound never curtailed its activity.  For instance, when aspirin or belladonna were used as crude plant extracts, their properties and potency were the same as today when we know the precise structure of their active ingredients: acetyl-salicylic acid, scopolamine, atropine, and I-hyosciamine. Transfer factor has been extensively used in animal and clinical studies since the early 70's in fighting or preventing infectious and parasitic diseases or cancer, and with unabated success.  There are over a thousand publications, some claiming dramatic clinical results that have never been challenged.  And although in science everything is possible (unexpected results and artefacts are common, as is subtle data falsification to conform to the paradigm of the day and to satisfy referees and statisticians), the surprising aspect of the TF saga is the lack of interest in solving the riddle, not because the claims have been found to be mistaken, but only because today's consensus does not allow for the existence of biologically active molecules with a non-defined structure, let alone their clinical use, which is considered anathema. Today's biomedical logic would rather that treatments were toxic than unintelligible. "For it is more respectable to reject a fact than to be mixed up with a fluke.  "And yet, in the TF story, we are not dealing with a spooky phenomenon of the paranormal eliciting "society's negative response, which leads individuals to suppress their experience for fear of rejection or ridicule"7, but with a clinically and experimentally well-documented reality"8. The most extraordinary placebo effect couldn't account for all the animal and  in vitro published data. Be that as it may, the clinical effects of TF deserve particularly today, closer examination.  For not only has this moiety the ability to instruct T lymphocytes to fight infections, but it can also be used for prevention, i.e. as a vaccine soliciting the cell mediated immunity, which plays a crucial role in infectious diseases.  When hundreds of millions of dollars are spent fighting bioterrorism, politicians and scientists with responsibilities in public health would be well advised to consider all possible answers to the challenges of the present, beyond preconceptions and experts' consensual support. A century before Kuhn's description of science revolutions, Huxley was calling "the slaying of a beautiful theory by an ugly fact, the great tragedy of Science"9.  It seems that, despite its history, science still resists the odd observation that does not make a priori sense, and for most scientists the unswerving commitment to the truth remains to this date an unattainable theoretical ambition. Only the power of mathematics and compelling experimental evidence forced the reluctant acceptance of the nonsensical, counterintuitive quanta world. Thus, in the name of modernity, scientists and physicians believe they are rejecting outdated reasoning, whereas in reality they are discarding facts and disdaining reality, all to the detriment of the patient.  For science is supposed to tackle strange phenomena, not ignore them because they defy consensual belief.  Hence, the sort of consensus that once applied to religious thought alone now pervades all activities of society, including scientific research.  And yet, from economics to terrorism, past experience should have gone some way to humbling the pundits, whose pretentious analyses are so often contradicted by the facts.  Only the comfort procured by certainty and herd psychology can possibly account for their irrational success. However, if in science observations suggesting phenomena evolving outside conventional thought deserve particular attention — they have always been the source of new insight and discoveries—, in medicine, accepting facts is more than a requirement of intellectual honesty, it is an ethically compelling necessity. Saving lives should be beyond rhetoric, bickering over theoretical considerations, bureaucracy, and even profit or political calculations. References Pizza G., et al. Tumour regression after intralesional injection of Interleukin-2 (IL2) in bladder cancer: preliminary report. Int J Cancer 1984; 34, 359-367. Rosenberg S.A., et al. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. New Engl J Med 1985; 313:1485-1492. a) Pizza G. et al. Interleukin-2 in the treatment of infiltrating bladder  cancer. J Exp Pathol 1987; 3:525-31. b) Lefesvre A., et al. Interleukin-2 treatment of lung metastasis of a mammary adenocarcinoma. J Exp Pathol 1987; 3:533-7. c) Pizza, G., et al. Intra-lymphatic administration of interleukin-2 (IL2) in cancer patients: a pilot study. Lymphokine Res, 7:4548-4551, 1988. d) Corrado, F., et al. Direct lymphatic immunotherapy for metastatic renal cell carcinoma. In: Immunotherapy of Renal Cell Carcinoma. Clinical and Experimental Development. Debruyne, et al. Eds, Springer-Verlag, Berlin, 1991:105-112. Pizza, G., et al. Immunotherapy of metastatic kidney cancer. Int J Cancer 94, 109-120, 2001 Negrier, S., et al. Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. N. Engl. J. Med. 1998; 338:1272-1278 Kirkpatrick, C.H., Transfer Factors: identification of conserved sequences in transfer factor molecules. Mol Med 2000; 6:332-41. van Lommel et al., Near-death experience in survivors of cardiac arrest : a prospective study in the Netherlands.  Lancet 2001; 2039-2045. G. Pizza, C. De Vinci, & D. Viza, Immunotherapeutic Approaches for Renal Cancer. Folia Biol 2002; 48: 167-181. Huxley, T.H., Collected essays.  "Biogenesis and Abiogenesis".