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March 7, 2000




Here's another addition to the tryptophan debate. A few months ago I wrote
a draft review on the 1989 tryptophan incident. It may, in a modified
form, later be published by the Task Group on Public Perceptions on
Biotechnology of the European Federation of Biotechnology. I am a member of
that Group.
Richard Braun
arations of the amino acid L-tryptophan,
widely used at that time in the US as a non-prescription medication. Since
the specific batches of L-tryptophan associated with EMS had mostly been
industrially produced in genetically modified bacteria, this incidence of
disease was ascribed by some people to the genetic modification of the
producer bacteria.


Between 1980 and 1989 L-tryptophan had been used extensively in the USA as
a freely available substance against insomnia, pre-menstrual syndrome and
depression. It was marketed as a food supplement, not as a drug. In the
autumn of 1989 clinicians observed a few patients with a disease showing a
combination of symptoms they had not seen before. Within weeks and with
the help of epidemiologists at the Center of Disease Control (Atlanta GE)
the incidence of this new disease could be traced to the consumption of
L-tryptophan made by one specific company, Showa-Denko of Japan, the major
producer world-wide. Over 1000 people became sick in a dose dependent
manner and 38 died (1, 2). The product was removed from the market and in
the intervening period of over ten years no new cases of EMS have occurred.
Some of those who had contracted EMS recovered, but there was still higher
mortality in those with EMS than in control groups. There was no evidence
of delayed onset of EMS in tryptophan users who were not already ill in
1989 (2). L-tryptophan was subsequently banned by the FDA as an
over-the-counter drug, while 5-Hydroxy-L-tryptophan is still freely
available. The latter compound has for many years been suspected to be
associated with some sporadic EMS-like cases (3).

Most of the preparations of tryptophan associated with EMS were made in a
transgenic strain of Bacillus amyloliquefaciens, strain V, which had been
developed to increase the yield of tryptophan. However, already previously
used strains were transgenic, and, what is more important, at the same time
as strain V was introduced, the purification scheme of the product was
shortened. The amount of active charcoal used to filter was halved and in
several batches another purification step, called ROM filtration (reverse
osmosis membrane filtration), was left out altogether. The new
L-tryptophan preparation, although still over 99% pure, was presumably less
pure than previous preparations.

It is obvious that the L-tryptophan preparations in question contained one
or more toxic contaminant which could have arisen either during processing,
purification and/or fermentation. Several contaminants, present in the
order of 0.01%, have been identified, for instance
1,1'-ethylidenebis(tryptophan) = EBT. Batches of the tryptophan derivative
5-Hydroxy-L-tryptophan, whether natural or synthetic, contain similar, but
not identical contaminants. The amount of EBT in the many Showa Denko
preparations of L-tryptophan was followed over a period of several years
and showed a marked peak in early 1989. This is consistent with the
hypothesis that a contaminant of L-tryptophan was responsible for EMS and
sporadic cases of a similar disease called EF which occurred between 1986
and 1988 (4). Showa-Denko claimed that the contaminants were not present
at the end of the fermentation and the company apparently does not have the
producer strains any longer, which makes a thorough study impossible. It
is plausible that the high yields during fermentation led to chemical or
enzymatic reactions resulting in minute amounts of toxic contaminants
during processing of fermentation products. In animal experiments none of
these compounds caused the symptoms of EMS and clinical studies also did
not lead to the definitive identification of the etiological agent. There
have not been any new outbreaks of EMS since 1989.

The EMS incidence of 1989 was clearly caused by a change in the
purification scheme of the amino acid tryptophan and/or in the producing
bacterial strains. This incidence highlights the importance of studying
the pharmacological effects of known substances, when introducing new ways
of preparing them. There is no evidence that the producer strain being
transgenic had any specific relevance to the EMS outbreak. Over 50
pharmaceuticals made by modern biotechnology are now available to consumers


1. A.N.Mayeno & G.J.Gleich, 1994:
Eosinophilia-myalgia syndrome and tryptophan production: a cautionary tale.
TIBTECH 12, 346 - 352

2. Report of the 19th Meeting of the Working Party on Applied Molecular
Genetics of the EFB, Uppsala, April 26-28, 1991.

3. E.A.Sullivan, M.L.Kamb, J.L.Jones, P.Meyer, R.M.Philen, H.Falk &
T.Sinks, 1996:
The natural history of eosinophilia-myalgia syndrome in a
tryptophan-exposed cohort in South Carolina.
Archives of Internal Medicine 156, 973 - 979

4. B.L.Williamson, K.Klarskov, A.J.Tomlinson, G.J.Gleich & S.Naylor, 1998:
Problems with over-the-counter 5-hydroxy-L-tryptophan.
Nature Medicine 4, 983

5. R.W.Martin, J.Duffy & J.T.Lie, 1991:
Mayo Clin. Proc.66, 892 - 898

* Prof. Richard Braun
* Enggisteinstrasse 19
* CH 3076 Worb
* T/F +41 31 832 00 00
* rdbraun@bluewin.ch