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From: ((Steven B. Harris))
Subject: Re: High Times at the Hilton--PWA questions Mullis
Date: 19 Jun 1995

In <3s3md5$> (Todd Miller
) writes:
>[snipped my comments about using Mullis to defend QC-PCR]
>>As in most things, Todd, and as with most Nobel prize winners, I
>>should think it would be much safer to trust Mullis in the area in
>>which he has expertise, and assign lesser credibility to him the
>>further from there he goes.
>>                                             Steve Harris, M.D.
>Oh, I see Steve.  You mean kind of like listening to Duesberg talk
>about retroviruses as opposed to Shockley talking about intelligence?
>Todd Miller, PhD


   Comment: Sure, we all know the sort of trouble Shockley got into.
As for Duesberg, you do bring up an interesting point.  Duesberg has
long been billed as a "retrovirologist."   A "virologist," however is
supposedly someone who knows a lot about viruses in general: their
structure, function, isolation, epidemiology, clinical manifestations,
lab animal experimental manipulation, molecular biology, etc.  Who
has taken classes in all those things, we would hope.  Someone like
Don Francis, or Luc Montagnier.   A "retrovirologist," if
there was a such a professional animal, would be a virologist
expected to know all this about retroviruses, of which there are
hundreds of types known.  Someone like Max Essex.

   But Duesberg's Ph.D. is in chemistry!  He has done considerable
molecular biochemistry (test tube stuff) on one odd type of retrovirus,
the Rous Sarcoma Virus (RSV), which as noted is in many ways not like
the others retroviruses (something we understand in no small part due
to Duesberg's work, in fact).  Duesberg's test tube experience with
RSV has given him no feel for what virologists, and even physicians
and biologists who work with infectious disease, know about the
pathophysiology of infection.  Or for what they know from running
experimental models of infection in animals, and or from observing
or treating viral infections in humans.

   So far as I can see, Duesberg's test-tube knowledge of RSV
has actually handicapped him, by making him look at the whole
world of retroviruses (and viral infections in general) through
"RSV glasses."  But these viruses aren't like RSV and they don't
behave like RSV.  Duesberg (Mr."in vitro") has decided that he
knows how retroviruses behave, but he demonstrates that he is almost
completely unfamiliar with the retrovirus experimental literature.
Or the oncovirus experimental literature.  He is convinced that
viruses (other than RSV) do not cause cancer, for instance.  But
what does he really know about woodchuck hepadnavirus experiments?
He is sure that lentiviruses cannot cause illness after an antibody
response, but what does he know about lentivirus animal experiments?
So far as I can see, the answer is: almost nothing!  Some

   As I noted here before, Duesberg's peculiar views as an
untrained self-styled "virologist" have given him some very
odd beliefs.  An outstanding example is his assertion in his
book that hepatitis C virus is just a plot by Chiron to make
everyone pay for a bogus blood test for something that doesn't
really exist (i.e., the "Lanka" approach to Hepatitis C).
But the hepatitis C agent has been fully cloned, sequenced,
grown in culture, electron micrographed, used to infect
monkeys and follow their immune responses with serology and
qc-PCR techniques.  There are a number of commercial first
and second generation lab tests for it.  It's not a retrovirus,
even, so it can hardly be claimed to be something that is
always there in the genome.  It's a simple RNA flavi-virus
related to yellow fever (another hepatic virus).  A vaccine
is expected shortly.  Yet all this again, in Duesberg's
mind, is a giant conspiracy-- another instance of science
failing to be self-correcting, the emperor having no clothes,
and corporate profits completely hiding reality from all
medical scientists everywhere, who (except for Duesberg) are
too dumb to know they've been had.

   Isn't it about time that we recognize this zaniness as the
as the Ross Perot type paranoia that it is?  Science does not
work this way.  Humans cannot keep large conspiracies secret.
And while we're at it: the trilateral commission is not
suppressing the AIDS-drug connection to increase their
Asian triangle profits through the CIA.  The government did
not invent HIV in a biowarfare experiment.  And Burroughs
Wellcome did not have a shooter on the grassy knoll in Dealy
Plaza.  Come on, people.

                                      Steve Harris, M.D.

From: (Steven B. Harris)
Subject: Primer: Chem 101, Pharm 101,  Doofusberg 101
Date: 05 Aug 1996

Dear MHA'ers:

   The recent debate on the concentration of AZT in one of
Duesberg's papers ("The toxicity of azidothymidine (AZT) on human
and animal cells in culture at concentrations used for antiviral
therapy," GENETICA volume 95, no 1-3, 1995) makes me realize that
the discussion may be passing over the heads of a few people.
Certainly it seems to have gone over the head of Todd, though I'm
not really sure how indicative that is.  At any rate, it seems
time for a primer.

   The problem is with the concentration of the drug AZT in this
paper, which Duesberg notes has been given to people at a dose of
20 to 60 micromoles per Kg per day.  A micromole is just a
measure of how many molecules of AZT are given (a micromole, or
1e-6 gram-atom, happens to be about 6e17 molecules).  20 to 60
micromoles per Kg per day simply says that this many micromoles
per day is given per Kg of patient.  Simple enough.

   The problem comes when Duesberg tries to figure out what
concentration of AZT this will result in, in a patient.  The
paper, after all does speak of the "concentration of AZT used for
antiviral therapy."  Duesberg would like to have a number for
this concentration, because many papers on toxicity, as well as
his own culture results, are done with AZT in concentrations of
micromoles per liter of cell culture fluid.  It is a good bet
(though not proved) that these concentrations of AZT in
culture result in about the same cell toxicity as the same number
of micromoles AZT per liter of body fluid, in a patient.  So the
$64,000 dollar question is: if we give one micromole AZT per Kg
of patient, does that result in a concentration of one micromole
AZT per liter of water IN the patient?

   Well, the short answer is that Duesberg assumes it does, in
his paper.  But unfortunately in the real world it does not, for
many reasons.

   One obvious reason that a micromole of AZT in a kilogram of
human does not result in the same concentration as if this much
AZT was dumped in a kilogram of pure water (about a liter), is
that a person isn't pure water.  A kilogram of person only has
about .5 to .6 Kg of water, and that's not the only problem.  For
many drugs (including AZT) the proteins in the part of the flesh
that isn't water, bind the drug.  There is a coefficient which
expresses this, and it is called the "volume of distribution."
The volume of distribution is simply how much pure water it takes
to replace a Kg of flesh, to get the same concentration of drug
as one gets when one actually puts the drug into a person.  If
the volume of distribution is 1 liter/Kg, that means that putting
the drug into a 70 Kg person results in the same concentration as
putting it into a 70 Kg beaker of water.  Volumes of distribution
for drugs can be low (.15 for aspirin, which is distributed only
outside of cells in interstitial water) or as high as 66 for
amiodarone (a heart drug, which binds heavily to non-water
components in tissue).  For AZT the volume of distribution is
1.6, which means that each Kg of patient acts like 1.6 liters of
water.  Thus, the concentration of AZT after an IV dose is only
1/3rd of what if would be if it simply remained in the body water
of the patient.

   Another problem for AZT is that the daily dose of 20 to 60
micromoles per Kg per day isn't give all at once, but divided
into 3 or as much as 6 doses (thus, as little as 3 uM per Kg per
dose).  The half life of the drug is so short (1 hour) that 99%
is gone by the time the next dose is administered, so each dose
is essentially starting over.  This effect cuts the peak
concentration of AZT by a factor equal to the number of doses.
For 3 doses per day, the peak concentration will only be 1/3rd of
what it would be if the daily dose were all given at once.  For 5
doses, it will be 1/5th of what it would be if the dose were
given all at once.

   Another factor is bioavailability.  Only 65% (on average) of
an AZT dose is absorbed by mouth, which means that only 65% of a
daily dose actually reaches the tissues.

   A last factor in peak AZT levels is the time it takes the drug
to be maximally absorbed from the gut to reach peak concentra-
tion.  This can be a large fraction of an hour, and during this
time the body is not simply storing up AZT, but also eliminating
it.  With a half-life of 1 hour, half the dose of AZT will be
eliminated while the dose is being absorbed, further cutting the
height of the peak.  Instead of pouring the dose into a beaker of
water, the picture is more near to pouring the drug into a sink
over an hour, while somebody lets half the water out via drain,
and somebody else fills the sink to a constant volume from a tap.

    All of these factors mean that a dose of 200 mg of AZT (750
micromoles or so) of AZT will not result in a peak AZT concentra-
tion of 750/50 = 15 micromoles per liter in a 50 Kg person, but
rather in a peak concentration of 15 uM offset by a factor of
1/1.6 for the volume of distribution, another .65 for the
biovailability, and perhaps another .5 for the elimination of
drug during absorbtion (giving perhaps 2.5 uM).  Actual measured
peaks are recorded anywhere from 1.5 to 10 micromoles per liter
for a 200 mg dose of AZT (many different sized persons included).
If 100 mg AZT is given five times a day rather than 200 mg three
times a day, then peaks are only half of this can be expected (5
uM to .75 uM depending on individual variation).  Average AZT
concentration will be considerably less, since half-life is
short.  None of these concentration numbers are anywhere near the
numbers that Duesberg uses in his paper for the expected
concentration of AZT in people taking AZT.  One would think that
Duesberg would actually look up what concentrations of AZT show
up in the blood of people in AZT therapy, for such an important
paper.  But he doesn't.  In short, Duesberg screws up.  As usual,
it takes a more than casual reader to catch him at it.  Which,
after all, is the reason for the success of Duesberg.

                                -- Steve Harris, M.D.

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