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
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.
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
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 –- 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
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
couldn't account for all the animal and in vitro
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
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
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 discoveriesó, in medicine, accepting
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.
- Pizza G., et
al. Tumour regression after intralesional injection of
Interleukin-2 (IL2) in bladder cancer: preliminary report.
Int J Cancer 1984;
- 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;
- a) Pizza G.
et al. Interleukin-2 in the treatment of infiltrating
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:
pilot study. Lymphokine Res, 7:4548-4551, 1988.
F., et al. Direct lymphatic immunotherapy for metastatic
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
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
- 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".