Tryptophan Summary

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Tryptophan Summary
 November 1997
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 this toxin.

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, 619, 1990.

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.