As we understand it, Dr
Steven Novella is an academic clinical neurologist at the Yale
University School of Medicine. He
maintains a widely-read blog ( https://www.sciencebasedmedicine.org/enbrel-for-stroke-and-alzheimers ) said to be motivated by medical skepticism
that since May 2013 has included his persisting negative opinion of the
pioneering approach used for the past 12 years or so by Dr Edward Tobinick and
his staff to treat neurodegenerative disease and neurogenic pain with
etanercept (enbrel). This treatment has
led to some 25 peer-reviewed papers authored by Tobinick, including an
internal-control case (i.e. detailed comparisons of pre and post-treatment
states) study of over 600 patients. All
of these publications advocate that double-blind trials should be performed to take this work
further. The scientific arguments on which it is based are well-known in the peer-reviewed
scientific literature, e.g. see http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4110406,
and are quoted objectively in the neuroscience literature, including by Yale-based
researchers. The patient welfare and commercial implications of such a treatment proving successful are obviously huge.
Novella maintains, indeed defends in court, that
his negative opinion is legitimate scientific criticism, made available on the web for general public
enlightenment, and protected as free speech. But facts matter in this field, and unfortunately his grasp
of basic uncontroversial science on display in his blog is, on the face of it, quite
fragmentary. It could have easily been
corrected by an hour’s diligence searching PubMed, the freely available Library
of Congress website. Examples
are given below. For his case
to be plausible, we demonstrate here, he would need to possess a much higher
standard of basic scientific competence in this area than his blog displays. We
also outline the motivation of a bigger picture within which Novella's blog
sits.
Scientific
replies to Novella’s criticisms
Example 1.
Novella’s criticism is based on misunderstanding a fundamental
property of TNF
Novella's widely
disseminated opinion that enbrel is a specific anti-inflammatory drug and is therefore
wrongly being used by Tobinick in neurological conditions not known to be
immune mediated is scientifically
quite wide of the mark. This makes many
of his criticisms groundless. In the brain, as elsewhere, TNF has in fact been
appreciated, for many years, to be just as large a player in normal physiology as
in inflammation and immunology, even though it may still routinely,
from tradition, be described as an inflammatory cytokine. Enbrel is one of the specific
anti-TNF agents, and at appropriate doses simply neutralizes excessive TNF. Lowering excess TNF levels in the brain in this
way restores a normal functional balance, or homeostatic equilibrium, and
therefore normal function is regained. This is very important in the brain,
particularly in synapses, the connections between neurons. TNF also controls production of glutamate, an
amino acid central to neurotransmission, particularly in synapses, but toxic in excess.
Example 2.
Novella’s
criticism of time of treatment since damaging event
Novella states: "Significant improvement was
noted [by Tobinick] irrespective of the length of time before treatment was
initiated; there was evidence of a strong treatment effect even in the subgroup
of patients treated more than 10 years after stroke and TBI. This, if anything,
is evidence that the observed treatment effect is mere placebo. It is very implausible
that stroke or TBI deficits will be equally responsive to an anti-inflammatory treatment
(or any treatment) regardless of time since the stroke or trauma."
In fact reactive microglia, the cells that generate excessive
TNF, have been shown to be present in stroke and trauma brains up to 17 years
after the event. See as examples, in peer-reviewed journals, Neurology 2000: 55; 1052-1054 and Brain 2013: 136; 28–42. These
authors discuss the concept of possible therapeutic intervention that Novella,
with the apparent weight of Yale’s Neurology Department behind him, criticizes
as implausible.
Example 3.
Novella’s criticism
of treating many cerebral conditions with one therapeutic agent
Through deprecating the concept of treating many
conditions with one therapeutic agent, Novella's blog content reveals no more
than fleeting reading of the scientific literature on TNF and chronic neurodegenerative
diseases. In 2015 a peer-reviewed text (Neuronal
Plasticity 2015:Article ID 358263, Open Access in PubMed, see http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4510439/pdf/NP2015-358263.pdf) gave reference, from the past 10 years, to 11 chronic brain disease
states (Alzheimer's disease, Parkinson's disease, Huntington disease, post-LPS
cognition, post-operative cognition, post-irradiation cognition, post-chemotherapy
cognition, rheumatoid arthritis cognition, sarcoidosis cognition, post-stroke
therapy, and traumatic brain injury) in which specific anti-TNF therapeutic
agents such as enbrel are in various stages of proposal and experimental development
for therapeutic use. This is part of a scientific
revolution in the genesis of disease of which Novella, as an academic, should
be concerned about advertising that he is unaware.
Comment on the
implication of the above three criticisms by Novella
Unfortunately, a peer reviewed article correcting such
fundamental errors as these three, which any reasonably-read neuroscientist
would recognize, would be ineffectual, since it could not hope to reach the target
audience of a widely accessed populist non-peer-reviewed blog. Thus much of the damage this blog causes to
the quality of knowledge acquired by its readers is very difficult to repair. Moreover, Novella’s blog has now had close to
three years to correct these errors, but shows no sign of doing so. In contrast,
genuine skeptics, such as scientists conscientiously seeking accuracy, closely
monitor the literature and evaluate it in order to acquire new knowledge that
allows them to maintain the health of the skepticism that is part of their job
description. Accordingly this present article, a one-off blog by researchers
who otherwise restrict their comments to the peer-reviewed literature, declares
Novella to be a pseudoskeptic with a non-scientific agenda, as discussed below.
Key elements of
the bigger picture
The second
intention of this article is to
acquaint readers with the outline of a bigger picture, of which Novella's blog is
but a part. His blog content cannot be
understood unless it is appreciated to be one of three like-motivated
linked strands of an orchestrated campaign to discredit Tobinick and his
approach to treating chronic neurodegenerative diseases at all costs.
Industrial scale
internet denigration campaign against Tobinick
The second
of the three strands, an
industrial scale internet denigration campaign directed against Tobinick's
publications in peer-reviewed journals has, in our experience, no
precedent. Currently, April 2016, Google
gives almost 1700 hits on Tobinick/fraud and almost 900 hits on Tobinick/quack. It is evidently orchestrated, with much of
the wording on Novella’s blog word for word, or paraphrased, in many similar
"fraud exposure" web pages, often with eye-catching bylines likely to
increase the hit rate.
An attempt to have Tobinick de-registered to practice medicine
The third of the three known strands of this interlinked
campaign began in June 2013 when a Dr Stephen Barrett made an official 25 page complaint
to the Medical Board of California, received at its Sacramento office on 27
June at 1.25pm, that Tobinick was involved in unprofessional conduct, and thus should
be disbarred from practice. Barrett is
an associate and co-author with Novella, for example on a joint
"Quackwatch" publication (see http://www.quackwatch.com/01QuackeryRelatedTopics/Cancer/conspiracy.html). In the face of evidence from independent academic neuroscientists
who had, in contrast to Novella or Barrett, observed patient outcomes at Tobinick’s
two clinics, this attempt to have him de-registered to practice medicine
failed, including on appeal (Medical
Board of California, Case No. 04-2012-222007, 22 May 2015).
Tellingly, as well as ruling no case to answer in terms of guilt, wrong-doing or
negligence, the Judge, the Honorable Samuel D. Reyes, found that this mode of treatment of neurodegenerative
disease with enbrel was a rational off-label approach. Specifically, the ruling, espoused by the
Medical Board of California, stated that there was “sufficient data and research
about the drug's safety and potential effectiveness to support the treatment
espoused by Dr. Tobinick.” The Medical Board of California issued an order withdrawing the accusation on June 16th 2015. Novella continues to maintain his professed opinion-based blog in the
face of, and without reference to, these court findings, which surely would
have influenced a genuine skeptic, as they did the Medical Board of California. Meanwhile, Tobinick's
Wikipedia entry has been extensively doctored, including removal of a summary of this court case outcome, by a group traceable to Novella. These individuals, in the words of a warning
by InvestmentWatch, http://investmentwatchblog.com/science-skeptics-use-guerilla-warfare-tactics-and-racketeering-behavior-to-infiltrate-wikipedia-and-spread-corporate-propaganda/" regularly use unprincipled behavior to edit Wikipedia.
Comment of these
three parallel strands of attack against Tobinick
In our
considered view these three interwoven attempts to discredit Tobinick: the
Novella blog that provides misinformation purporting to have Yale backing; the
large continuing internet campaign; and attempting through the courts to have
him barred from practicing (even to the extent of taking the trouble and
expense to appeal against the Judge's initial decision) are, in terms of
intent, complexity and cost, far beyond the usual scale of website denigration
of medical practitioners that the public have come to expect from Novella. It also allows the public to see Novella's
blog in a much more serious light than merely as an isolated personal opinion
expressing what he defends as legitimate scientific criticism.
How might
all this have come about? A comparison with the origins of the first use of an enbrel-like
agent in a human disease in 1993 is instructive. The steps in this process followed what
patients should expect, and indeed demand, as standard procedure. In that
year a comparably small but startling open trial with the first specific biological
anti-TNF agent, remicade, to treat rheumatoid arthritis was reported (see Arthritis and Rheumatism 1993: 36;
1681-1690). Without any equivalent
of the web attack, derogatory blog, and accusations in court meted out for
years to Tobinick, it was formally tested through an industry-funded random
double-blind study by the same researchers, using their original protocol, the very
next year (see Lancet
1994: 344; 1105-1110). Thus the first practical, FDA-approved, use
of an anti-TNF therapy began.
The key question, still unresolved, is why
Tobinick's equally startling open trial of a similar size and duration using enbrel
against a neurodegenerative disease, by a novel administrative route he developed
(See Medscape General Medicine Neurology and Neurosurgery 2006: 8; 25), did
not followed the same path as did remicade for treating rheumatoid arthritis. Instead, and as yet unaccountably, the makers of
enbrel formally distanced themselves from Tobinick's open trial, leaving, as is
often the case, off-label treatment as an interim until controlled trials are
funded. As described above, this has
been met by a combined attack consisting of (a) large scale internet derision, begun
in 2008 and still present (b) the Novella blog, begun in 2013 and still present,
and (c) an attempt to de-register Tobinick through the courts, begun in December
2014 and dismissed in May 2015. All this
implies a financial
backer prepared to go far on several fronts.
To
understand how much patients and neuroscience stand to lose should Tobinick not prevail against this attack, which has actively prevented his method of delivery being formally tested for years, and tried to shut him down, the
reader must understand that the battle is actually about possession of a technique to get
large therapeutic molecules through the blood-brain barrier, a
widely-sought goal. Never mentioned by Novella, this is the logical
driving force behind all three lines of attack on Tobinick (see Drug Discovery Today 2009: 14; 168-177 and Bioengineering Bugs 2010: 1; 231-234). An internet search finds an example of a large
well-funded investor consortium whose
current goal is to develop a technology for this purpose (see
http://www.prnewswire.com/news-releases/armagen-technologies-inc-announces-17-million-series-a-financing-181460481.html). Should Tobinick's novel route of injection – used in his patients long before this consortium's modified enbrel was used experimentally
in mice, and convincingly logical to qualified witnesses who defended him and thence the
Judge who presided over the Medical Board of California case No. 04-2012-222007 cited earlier – be
formally trialed and accepted, the need for the consortium's technology probably
no longer exists, placing its investors in jeopardy. This is a compelling example of a motivation
to fund discrediting Tobinick's work (which is applicable to getting many other large molecules into the brain) on as many fronts as possible, no expense
spared.
Actions from within the university associated with this investor consortium
It is not likely to be coincidental
that the medical school department hosting this investor consortium's research
funding (see Crossing the Barrier in http://www.neurology.ucla.edu/research/programs/stroke) to allow it to adapt Tobinick's
unacknowledged findings to Trojan Horse delivery technology, is the very one
from whence was hatched the plan to terminate his work through the above court
case. In contrast,
the university itself has praised the advance that Tobinick's work represents (see http://www.newsroom.ucla.edu/in-the-news/ucla-headlines-jan-11-2008-43001). This did not prevent written claims from this university department that Tobinick was a fraud and a quack, and that his treatment of stroke with enbrel was scientifically unsound, being systematically distributed to the clinical neurology world and to journalists, even after Tobinick's peer-reviewed study of over 600 patients before and after treatment had been published (see CNS Drugs 26: 1051-1070, 2012 at http://www.ncbi.nlm.nih.gov/pubmed/23100196). In addition, others within the same university had published an in-principle mouse Trojan Horse study (see J Cereb Blood Flow Metab 32: 1933-1938, 2012) that was consistent with Tobinick's earlier results, so recipients of these claims were being knowingly misled. As noted above, the content of Novella’s blog regarding Tobinick, claimed to be written in the interests of science-based medicine, falls very short of accepted international academic standards. Recall that neither Novella, nor any of the people who brought and made the failed case against Tobinick through the Californian Medical Board, has ever observed the outcome of treatment. Hence, as part of a wider pattern of events designed to denigrate Tobinick and his work, the content of this Novella's blog can be validly described as malicious intent, for commercial reasons, posing as genuine ignorance allowable as harmless free speech. This Novella blog is part of a wider pattern of activity that can be characterized as orchestrated, without regard for scientific fact or patient welfare, for extremely large-scale financial gain. Clearly, the intent of Novella's blog, is, as was bringing the California court case outlined above, to deny Tobinick credit for and involvement in a treatment route he pioneered over a decade ago, and to halt its formal development. This would close down a sorely-needed advance towards effective patient care for otherwise untreatable long-term neurodegenerative conditions.
Summary
As
demonstrated above, the scientific standard of Novella's blog is unacceptable as the genuine knowledge level of someone the
internet describes as a Yale-based academic clinical
neurologist informing the public for altruistic reason. For a genuine
skeptic, it would be an academic embarrassment. This widely disseminated erroneous material appears to be intended to
influence lay people who might otherwise be philanthropic towards funding a
random double blind trial based on Tobinick's approach, or families of patients
who might otherwise volunteer to take part in such a trial, or ask for
off-label treatment. Meanwhile,
Novella's blog argues that Tobinick's treatment is meaningless until the very
trial Novella is actively discouraging through his blog has been done.
Novella's
blog is to be viewed as part of a plan to shut down a small scale player who
has developed a key original idea, and is attempting to follow it through the
correct procedures to have it registered as an approved treatment. Since it shows every sign of promise in 1000s
of off-label treatments, it has, if left to develop undisturbed, the potential
to help very many patients and their families.
As a side effect it would put a very large competitor, later than Tobinick
on the TNF/neurodegenerative disease scene, in jeopardy. It is most disturbing that ousting
competitors is considered by some as infinitely more important than helping present
patients and their families, as well as advancing neuroscience for the benefit
of future patients.
By a group of academic TNF
scientists with no commercial interest in this matter.
