JOHN B. FAGAN, PH.D.
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 tryptophan
production. They genetically engineered bacteria by inserting several genes
that caused the bacteria to express certain enzymes at much higher levels
than normal and to express other enzymes that are not normally present in
the original bacteria.
The enzymes expressed in these bacteria through genetic engineering altered
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. According to US law, Showa Denko was allowed to
sell the tryptophan produced in genetically engineered bacteria without
safety testing because they and other companies had been selling tryptophan
produced in non-genetically engineered bacteria for years without ill
effects. It was considered 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. In effect they considered it substantially equivalent to the
tryptophan that had been sold for many years.
This product was placed on the market, and within a few months it caused
the deaths of 37 people and caused 1500 more to be permanently disabled
(1). It took months to discover that the poisoning was due to toxin present
in the tryptophan produced using Showa Denko's genetically engineered
bacteria (1, 2). One factor that contributed to this time delay was the
fact that the product was not labeled to distinguish it from tryptophan
produced through conventional methods.
The disease caused by this toxic product was called eosinophilia myalgia
syndrome or EMS, because the initial symptoms were elevated numbers of
blood cells called eosinophils and myalgia (muscle pain). Over time many
other symptoms developed in patients that led in some cases to death and in
many other cases to serious long term disability. These symptoms included
paralysis and neurological problems, painful swelling and cracking of the
skin, heart problems, memory and cognitive deficits, headaches, extreme
light sensitivity, fatigue, and heart problems (3,4).
It was later shown that the tryptophan produced in genetically engineered
bacteria contained one or more highly toxic contaminants. The most
prominent of these, called EBT, was identified as a dimerization product of
tryptophan. It comprised less than 0.1% of the total weight of the product,
yet that was enough to kill people (1). 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 (5). Thus, it appears that genetic
manipulationsled 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.
Showa Denko has never released the genetically engineered bacterial strain
that was used to produce the toxic tryptophan. Thus, independent scientists
have been unable to study its characteristics and understand precisely the
source of the toxin. Showa Denko claim that they destroyed all stocks of
the bacteria when the toxicity problems first began to emerge (2). Such
research would not only have provided data useful in assessment of the
risks of genetically engineered organisms, but it would also have been
useful to victims of tryptophan toxicity and their families, who eventually
filed suits totaling over two billion dollars against this company.
From the research that has been done (reviewed in ref. 1), these facts are
clear: (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 also cut corners in
the purification procedure used in preparing most of the toxic batches of
tryptophan, reducing the amount of activated charcoal used in filtering the
tryptophan from 20 to 10 kilograms per batch.
Unfortunately, the body of published research (more than 200 studies) does
not definitively establish whether toxicity resulted primarily from the use
of genetically engineered bacteria or from cutting corners in the
purification procedure. The status of this question is expressed in the
following quote from Science (2):
"Regardless of the legal details, the crux of the EMS case remains the
issue of whether the disease is, in fact, due to genetic engineering. At
the same time Showa Denko began using its new, genetically engineered
bacillus (known as Strain V), it also reduced the amount of activated
carbon used to filter the fermentation broth from 20 to 10 kilograms per
batch-suggesting that inadequate filtration might have allowed impurities
to pass through."
"That possibility is discounted by scientists at Showa Denko, says Richard
Hinds, a Washington lawyer who represents the Japanese firm. The amount of
powdered carbon used for filtration had varied before without ill effect,
and it was not unusual for it to dip this low, Hinds says."
Genetic engineering is also implicated by two additional facts: (a) The
toxin has never been shown to be present in the original, non-genetically
engineered bacteria. If the non-genetically engineered bacteria do not
produce the toxin, it would seem likely that genetic engineering conferred
the ability to produce the toxin. (b) Tryptophan produced by other
manufacturers, who have been using non-genetically engineered bacteria, has
never led to outbreaks of EMS, even though these manufacturers are also
likely to cut corners in their purification procedures from time to time,
as Showa Denko did. Based on these points, we conclude that it is highly
likely that genetic engineering was the determining factor in generating
1. Mayeno, A.N. and Gleich, G.J., Eosinophilia-myalgia syndrome and
tryptophan production: a cautionary tale, TIBTECH, 12, 346-352, 1994.
2. Raphals, P., Does medical mystery threaten biotech? Science, 249,
3. Brenneman, D.E., Page, S.W., Schultzberg, M., Thomas, F.S.,
Zelazowski, P., Burnet, P., Avidor, R., and Sternberg, E.M., A
decomposition product of a contaminant implicated in l-tryptophan
eosinophilia myalgia syndrome affects spinal cord neuronal cell death and
survival through stereospecific, maturation and partly
interleukin-1-dependent mechanisms, Journal of Pharmacology and
Experimental Therapeutics, 266(2), 1029-1035, 1993.
4. Love, L.A., Rader, J.I., Crofford, L.J., Raybourne, R.B.,
Principato, M.A., Page, S.W., Trucksess, M.W., Smith, M.J., Dugan, E.M.,
Turner, M.L., Zelazowski, E., Zelazowski, P., and Sternberg, E.M.,
Pathological and immunological effects of ingesting l-tryptophan and 1,
1'-ethylidenebis (l-tryptophan) in Lewis rats, Journal of Clinical
Investigation, Inc., 91, 804-811, March 1993.
5. Raphals, P., EMS deaths: Is recombinant DNA technology involved?,
The Medical Post, Maclean-Hunter, Toronto, 16, November 6, 1990.
Food - Safety Problems"
Published by PSRAST