Ph.D. John Fagan
Food supplements, such as amino acids, are
often manufactured by
fermentative processes, in which large quantities of bacteria are
grown in
vats, and the food supplement is extracted from the bacteria and
purified.
One amino acid, tryptophan has been produced in this way for many
years. In
the late 1980's the company Showa Denko K.K. decided to use
genetic
engineering to accelerate and increase the efficiency of the
production
process. They genetically engineered bacteria by inserting new
genes that
caused the bacteria to express new enzymes.
The enzymes expressed in these bacteria
through genetic engineering were
not present in massive amounts, but they altered the cellular
metabolism
substantially, leading to greatly increased production of
tryptophan. These
genetically engineered bacteria were immediately used in
commercial
production of tryptophan, and the product placed on the market in
the USA
in 1988. The Food and Drug Administration allowed Showa Denko to
sell this
genetically engineered product without safety testing because
they and
other companies had been selling tryptophan, produced in
non-genetically
engineered bacteria, for quite some time without ill effects. It
was argued
that the method of production (whether via natural or genetically
engineered bacteria) was immaterial and that, since tryptophan
had already
been shown to be safe, the new material needed no testing.
Furthermore, FDA
regulations did not require that the new tryptophan be labeled as
genetically engineered.
This product was placed on the market in
the late 80's, and within three
months, 37 people died and 1500 were permanently disabled from
using this
product. It took months to discover that the poisoning was due to
toxins
present in the new genetically engineered tryptophan. One factor
that
contributed to the time delay was the fact that the product was
not labeled
as genetically engineered.
The disease caused by this toxic product
was called eosinophilia myalgia or
EMS, because the initial symptoms were high numbers of a certain
kind of
blood cell called eosinophils and myalgia or muscle pain.
However, over
time a large number of symptoms developed in patients that led in
some
cases to death and in many other cases to serious long term
debility. In
addition to increased eosinophil numbers and myalgia, these
symptoms
included paralysis and neurological problems, painful swelling
and cracking
of the skin, heart problems, memory and cognitive deficits,
headaches and
extreme light sensitivity, fatigue, heart problems, and many
other
difficulties.
It was later shown that the genetically
engineered tryptophan contained one
or more highly toxic contaminants. The most important
contaminant, called
EBT, was identified as a dimerization product of tryptophan-two
molecules
of tryptophan chemically linked together. It comprised less than
0.1% of
the total weight of the product, yet that was enough to kill
people. Based
on fundamental chemical and biochemical principles, scientists
have deduced
that this compound was probably generated when the concentration
of
tryptophan within the bacteria reached such high levels that
tryptophan
molecules or their precursors began to react with each other.
Thus, it
appears that genetic manipulations led to increased tryptophan
biosynthesis, which led to increased cellular levels of
tryptophan and
precursors. At these high levels, these compounds reacted with
themselves,
generating a deadly toxin. Being chemically quite similar to
tryptophan,
this toxin was not easily separated from tryptophan, and
contaminated the
final commercial product at levels that were highly toxic to
consumers.
Significant areas of ambiguity remain even
today regarding this incident,
because it was quite threatening to a number of parties,
including Showa
Denko, the FDA, the biotechnology industry, and the food
supplement
industry. Obviously, it was in the best interests of these
parties to
minimize public awareness and discussion regarding the incident,
and to
avoid in-depth definitive scientific research on its cause. In
depth
research was a threat to Showa Denko because it might have
provided
information useful to victims and their families, who eventually
filed
suits totaling over two billion dollars against this company. Any
kind of
further debate on this incident, such as that which in depth
research would
have generated, was unwanted by the FDA, because the incident
exposed
weaknesses and inadequacies in the FDA's food safety testing
system. The
biotechnology industry wanted to avoid in depth research because
it
threatened to conclusively demonstrate that it was, in fact the
process of
genetic engineering that was responsible for generating this
deadly
product, thus making the tryptophan incident an incontrovertible
example
that genetic engineering can generate unsafe foods and drugs (ref
1). The
food supplement industry was threatened because it was, after
all, a food
supplement that killed people.
From the research that has been done
(reviewed in ref. 2), these facts are
clearly established: (a) Batches of tryptophan produced by only
one
company, Showa Denko, were toxic. (b) These batches of tryptophan
contained
the contaminant EBT and possibly other compounds that are highly
toxic and
give rise to EMS-like symptoms when fed to rats. (c) Showa Denko
had used
genetically engineered bacteria in the fermentation process by
which the
toxic batches of tryptophan had been produced. (d) Showa Denko
had cut
corners in the purification procedure used in preparing most of
the toxic
batches of tryptophan. They had reduced the amount of activated
charcoal
used in filtering the tryptophan from 20 to 10 kilograms per
batch.
Unfortunately, the published research does
not definitively establish
whether toxicity resulted primarily from the use of genetically
engineered
bacteria or from cutting corners in the purification procedure.
A definitive answer to this question cannot
be obtained, because it is
impossible to reproduce the production process that Showa Denko
used. This
is because Showa Denko claims to have destroyed all samples of
the
genetically engineered bacteria and thus samples of this
bacterium are not
available for in-depth study.
Two lines of indirect evidence do clarify
this question, however, and
suggest that genetic engineering is the most likely source of
these toxins:
(a) The toxin has not been shown to be present in the original,
non-genetically engineered bacteria. If the non-genetically
engineered
bacteria cannot produce the toxin, it must be that genetic
engineering
conferred on these bacteria the ability to produce the toxin. (b)
Showa
Denko lawyers claim that their scientists discount the
possibility that
changes in the purification are to blame (ref 3). They say that
before they
began to use genetically engineered bacteria in tryptophan
production, the
amount of charcoal used in tryptophan purification varied
substantially and
often dropped as low as 10 kilograms per batch. Yet, those
batches of
tryptophan were not toxic. Furthermore, tryptophan produced by
other
manufacturers, who have been using natural bacteria, has not been
toxic,
even though these manufacturers also cut corners in their
purification
procedures from time to time. Based on these points, we conclude
that it is
likely that genetic engineering was the determining factor in
generating
this toxin.
References
1. L-Tryptophan Puzzle Takes New Twist,
Science, vol 249, page 988, 31
August 1990
2. EMS and Tryptophan Production: A Cautionary Tale, TIBTECH, vol
12
pages 346-352, September 1994.
3. Does Medical Mystery Threaten Biotech? Science, page 619, 2
November 1990
John B. Fagan, Ph.D.
Professor of Molecular Biology
Maharishi University of Management
(Maharishi International University 1971 to 1995)
1000 North Fourth Street
Fairfield, Iowa, 52557-1078
Phone(515) 472-8342
Fax (515) 472-5725
email jfagan@mum.edu
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Valmistunut 13.3.1997