GENTECH archive 8.96-97

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L-tryptophan



About L-tryptophan, 37 deaths and 1500 permanent disabilities are tragic
under any circumstances.  But is genetic engineering to blame?    I
received John Fagan's report on tryptophan from rwolfson@concentric.net
(Richard Wolfson).  I show at the end of this message Fagan's report in its
entirety.  One of the key paragraphs of the report comes near its end:

Fagan: "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."

In fact, the most recent and thorough review cited by Fagan suggests that
the most likely cause was a problem in purification (see reference 2 cited
below).  Not only was less activated carbon used in purification, there
were also some batches that did not get processed through a reverse osmosis
filter.  In particular, according to this paper, "the clinical  and
pathological findings of EMS bear a striking resemblance to those of toxic
oil syndrome".... an outbreak resulting from illegally processed rapeseed
oil which killed 839 people.  Rather than the EBT described by Fagan, the
most suspicious contaminant of the tryptophan was 3-(phenylamino)-L-alanine
(PAA), which is very similar to 3-phenylamino-1,2 propanediol (PAP), a
suspect compound found in the rapeseed oil.

As noted in reference 2, this case highlights the need for close monitoring
of chemical purity.  However, reference 2, written by scientists who
actually worked on the problem, does not even  suggest genetic engineering
as a cause.

You would ban transgenic crops on the basis of this case?  Don't take my
word or that of Fagan; read the papers cited by Fagan, especially ref 2.  I
hope that you will be impressed that quite detailed and in-depth
scientific research was actually done in this case.

Rick



Summary of the Tryptophan Toxicity Incident John 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 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 (Trends
in Biotechnology), vol 12 pages 346-352, September 1994.
3.      Does Medical Mystery Threaten Biotech? Science, page 619, 2
November 1990