Flacherie (and a ridiculous history of Bt development…roundabout)

January 26, 2024
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History of Bt Development as told in New Innovative Pesticides: An Evaluation of Incentives and Disincentives for Commercial Development by Industry, Stanford Research Institute (Final Report dated September 1977, Prepared for Economic Analysis Branch Criteria and Evaluation Division Office of Pesticide Programs US Environmental Protection Agency Washington DC)

Punctuation if nothing else may be wonky because this is copied and pasted from google books

The history of Bt development as a microbial insecticide prior to the discovery of the improved HD 1 strain is extensive. See Norris 1967 and Heimpel 1967. The bacterium was first isolated in Japan in 1902 by Ishiwata from silkworms suffering from an epidemic flacherie. Beyond its devastating effect on commercial silkworm populations little thought was apparently given at that time to its potential as a microbial insecticide. In 1915 the bacterium was re examined and named Bacillus sotto. Two strains were differentiated based upon their pathogenicity to silkworm. At about the same time Berliner was isolating the organism from larvae of the flour moth Anagusta kuhniella. He independently named the bacterium Bacillus thuringiensis the currently accepted binomial and hence became the authority of record. With its reisolation in 1927 Bt first began to receive attention as a potential insecticide. During the 1930s demonstration of its wide host range prompted extensive testing in Europe. Promising results against the European corn borer Ostrinia nubilalis were obtained. Immediately prior to the outbreak of World War II the first commercial Bt based insecticide Sporeine was produced in France.

Obviously that grabbed my attention but what in the effity eff is the rest of this stuff?

American interest in Bt grew after World War II and impressive levels of control against the alfalfa caterpillar Colias eurytheme were obtained in field trials. In 1953 additional interest was stimulated by Hannay’s demonstration in Canada of the role of the specific crystalline endotoxin, although the presence of the proteinaceous crystals had been observed early in the history of Bt their toxicological character had not been suspected. Previously the insecticidal activity of Bt preparations had been assumed to result from massive pervasion of host tissues by a burgeoning bacterial population The uncovering of this specific contained toxic agent provided a new dimension to insect pathology and expanded the commercial development potential of Bt. The first commercial Bt insecticide in the United States became available in 1958. Added impetus for development was provided in 1966 when the federal government banned a series of chemical insecticides from use in the control of worms on tobacco because of toxic residue problems. Bt was recommended as a substitute and it subsequently provided reasonable control of tobacco hornworm Manduca sexta and tobacco budworm Heliothis virescens (since renamed/reclassified and recently discussed in one of these notes). However in spite of several demonstrations of effectiveness in insect control use of Bt prior to 1969 proved in many instances to be unreliable because of variability in potency that was generally characteristic of the commercial preparations then in use. Because of this experience Bt came to be viewed with suspicion by some authorities. In 1969 a new strain was discovered by Dr Howard Dulmage USDA at Brownsville Texas which displayed a potency 15 to 30 times higher than previous formulations. The new strain designated HD 1 provided a higher and more reliable degree of control and was rapidly incorporated into commercial formulations. Adequate methods of product standardization were subsequently developed by Dr Dulmage et al and were adopted by industry. Today all commercial preparations of Bt are based upon the HD 1 strain and research is underway to develop still more potent strains The three primary US producers of Bt are Abbott Laboratories, Nutrilite Products Inc and Sandoz Inc owned by Sandoz AG Switzerland. Abbott Laboratories produces a wettable powder formulation labeled DipelR which can also be formulated as a baited insecticide by mixing with corn meal. Sandoz the other major domestic producer manufactures both a flowable liquid formulation and a wettable powder formulation labeled Thuricide Sandoz’s package of Bt technology was purchased in 1973 from the International Minerals & Chemical Corp. Nutrilite Products Inc produces smaller quantities of Bt in a wettable formulation under a Biotrol trademark these products are exclusively distributed by the Thompson Hayward Chemical Co which also markets a corn meal corn oil baited formulation.

New Innovative Pesticides: An Evaluation of Incentives and Disincentives for Commercial Development by Industry, Stanford Research Institute, Final Report September 1977, Prepared for Economic Analysis Branch Criteria and Evaluation Division Office of Pesticide Programs US Environmental Protection Agency Washington DC

As far as I can tell, Nutrilite is an Amway company.

So Sandoz…what on earth?

Sandoz Group AG is a Swiss-Germany based company that focuses on generic pharmaceuticals and biosimilars. Prior to October 2023, it was part of a division of Novartis that was established in 2003, when Novartis united all of its generics businesses under the name Sandoz. Before this, the company existed as an independent pharmaceutical manufacturer until 1996, when it was merged with Ciba-Geigy to form the company Novartis. Prior to the merger, it specialized in medicines used in organ transplants, such as Sandimmune, and various antipsychotics and migraine medicines. Its headquarters were in Holzkirchen, Germany and after the spin-off from Novartis, the headquarters moved to Basel, Switzerland. Sandoz is one of the leading global generics business.

1886–1995: Formation and initial growth

The company was founded in 1886 by Alfred Kern (1850–1893) and Edouard Sandoz (1853–1928) in Basel (Switzerland) under the name Chemiefirma Kern und Sandoz. Initially the company focused on production of dyes namely alizarin blue and auramine. When Kern died, the company changed its name to Chemische Fabrik vormals Sandoz in 1895 and began producing pharmaceuticals for the first time the same year. As early as 1895, the first pharmaceutical substance called antipyrine was produced to reduce fever. In 1899 they started producing saccharin. Well damn…or ring a ding ding…or something

Phenazone (also known as phenazon, antipyrine, antipyrin, or analgesine) is an analgesic (pain reducing), antipyretic (fever reducing) and anti-inflammatory drug. While it predates the term, it is often classified as a nonsteroidal anti-inflammatory drug (NSAID). Phenazone was one of the earliest synthetic medications — when it was patented in 1883, the only synthetic medical chemicals on the market were chloral hydrate, a sedative (as well as at least one derivative of that chemical), trimethylamine, and iodol (tetraiodopyrrol), an early antiseptic. One of the earliest widely used analgesics and antipyretics, phenazone was gradually replaced in common use by other medications including phenacetin (itself later withdrawn because of safety concerns), aspirin, paracetamol and modern NSAIDs such as ibuprofen. However, it is still available in several countries either as an over-the-counter or prescribed drug.

Phenazone is synthesized by condensation of phenylhydrazine and ethyl acetoacetate under basic conditions and methylation of the resulting intermediate compound 1-phenyl-3-methylpyrazolone with dimethyl sulfate or methyl iodide. It crystallizes in needles which melt at 156 °C (313 °F). Potassium permanganate oxidizes it to pyridazine tetracarboxylic acid.

Possible adverse effects include:[citation needed]

Phenazone is often used in testing the effects of other drugs or diseases on drug-metabolizing enzymes in the liver. Go figure.

Arthur Stoll – Together with Sandoz employees, he developed a range of methods for producing drugs. Thus, he developed the first isolation of ergot alkaloids (as ergotamine and ergobasine) and cardiac glycosides, which are used as a medicine for heart diseases and migraines. A continuous process for the production of soluble calcium salts was developed. He worked with Albert Hofmann.

In 1917, Sandoz entered pharmaceutical research when Arthur Stoll (1887–1971) was hired, and, in 1929, Calcium Sandoz was introduced, laying the foundation research into modern calcium therapy. In 1918, Arthur Stoll isolated ergotamine from ergot; the substance was eventually used to treat migraine and headaches and was introduced under the trade name Gynergen in 1921.

This was not a new trick. See Ergotism.

Ergotamine is a secondary metabolite (natural product) and the principal alkaloid produced by the ergot fungus, Claviceps purpurea, and related fungi in the family Clavicipitaceae. Its biosynthesis in these fungi requires the amino acidL–tryptophan and dimethylallyl pyrophosphate. These precursor compounds are the substrates for the enzyme, tryptophan dimethylallyltransferase, catalyzing the first step in ergot alkaloid biosynthesis, i.e., the prenylation of L-tryptophan. Further reactions, involving methyltransferase and oxygenase enzymes, yield the ergoline, lysergic acid. Lysergic acid (LA) is the substrate of lysergyl peptide synthetase, a nonribosomal peptide synthetase, which covalently links LA to the amino acids, L–alanine, L–proline, and L–phenylalanine. Enzyme-catalyzed or spontaneous cyclizations, oxygenations/oxidations, and isomerizations at selected residues precede, and give rise to, formation of ergotamine.

Albert Hofmann in 2006

In 1938 Albert Hofmann produced the synthetic substance lysergic acid diethylamide, better known as LSD. The psychoactive properties of this preparation were nevertheless not discovered until 1943, when Hofmann ingested a small amount by accident. From 1947 to the mid-60s, LSD was sold by Sandoz under the name Delysid . It was marketed as a treatment for a wide variety of mental ailments, ranging from alcoholism to sexual deviancy. Sandoz suggested in its marketing literature that psychiatrists take LSD themselves, to gain a better subjective understanding of the schizophrenic experience, and many did exactly that and so did other scientific researchers. The Sandoz product received mass publicity as early as 1954, in a Time magazine feature. Research on LSD peaked in the 1950s and early 1960s.

The CIA purchased quantities of LSD from Sandoz for use in its illegal human experimentation program known as MKUltra. Sandoz withdrew the drug from the market in 1965. The drug became a cultural novelty of the 1960s after psychologist Timothy Leary at Harvard University began to promote its use for recreational and spiritual experiences among the general public.

Swiss chemist and pharmacist Albert Wander (1867–1950) developed Ovomaltine in 1904.

In 1939, Kern & Sandoz became Sandoz Ltd., a name it operated under for nearly sixty years. In 1963, Sandoz acquired Biochemie GmbH, which was producing and supplying scarce, urgently needed acid-resistant penicillin. In 1967, Sandoz merged with Wander AG and diversified into the dietetics business with Ovomaltine and Isostar.

Ovaltine (also known by its original name Ovomaltine) is a brand of milk flavoring product made with malt extract (except in the blue packaging in the United States), sugar (except in Switzerland), and whey. Some flavors also have cocoa. Ovaltine, a registered trademark of Associated British Foods, is made by Wander AG, a subsidiary of Twinings, which acquired the brand from Novartis in 2002, except in the United States, where Nestlé acquired the rights separately from Novartis in the late 2000s. Ovaltine was developed in 1904 by chemist Albert Wander [de] (1867–1950), in Bern, Switzerland, where it is also known by its original name, Ovomaltine (from ovum, Latin for “egg”, and malt, which were originally its key ingredients). In 1927, the factory moved out to the village of Neuenegg, a short distance west of Bern, where it is still produced.

Isostar is a sports drink sold in Europe. It is similar to Gatorade and Powerade in that it hydrates and provides energy through glucose. Isostar was first created in Switzerland in 1977.

In 1972, Sandoz acquired Delmark, Wasabröd, Wasa, the Swedish crisp bread producer Wasa in 1982. In 1986, Velsicol Chemical Corporation acquired the agrochemicals division of Sandoz. In 1994, Sandoz bought Gerber Products Company, expanding its research into biopharmacueticals. Dear God. In 1995, the specialty chemicals division became an independent company under the name Clariant, based in Muttenz.

There is more here but I think that’s quite enough for now.

The original subject matter was this pox of the silkworm…

Flacherie (literally: “flaccidness”) is a disease of silkworms, caused by silkworms eating infected or contaminated mulberry leaves. Flacherie infected silkworms look weak and can die from this disease. Silkworm larvae that are about to die from Flacherie are a dark brown.

There are two kinds of flacherie: essentially, infectious (viral) flacherie and noninfectious (touffée) flacherie. Both are technically a lethal diarrhea.

Touffée flacherie is caused by heat waves.

  • Fernando E. Vega and Harry K. Kaya, Academic Press, 2012,p. 427, online.

Viral flacherie is ultimately caused by infection with Bombyx mori infectious flacherie virus (BmIFV, Iflaviridae), Bombyx mori densovirus (BmDNV, Parvoviridae) or Bombyx mori cypovirus 1 (BmCPV-1, Reoviridae). This either alone or in combination with bacterial infection destroys the gut tissue. Bacterial pathogens contributing to infectious flaccherie are Serratia marcescens, and species of Streptococcus and Staphylococcus in the form known as thatte roga.

In the nineteenth century, flacherie resisted the efforts of Louis Pasteur.

  • G. Balbiani, Leçons sus les sporozoaires, Paris, 1884, p. 160-163 and 167-168, online.

In 1870, Pasteur had reported that a coccus and bacillus bacteria caused the flacherie in silkworms. Other researchers have reported that different bacteria are causing bacteriosis in silkworms.

  • Cuboni and Garibini (1890) thought that Bacillus cubonianus was the cause of flacherie.
  • In Japan, the causal agent of Sotto disease was identified as Bacillus sotto (Iwashita, 1902), which presently is known as Bacillus thuringiensis var. sotto.
  • Sawamura in 1960 isolated Bacillus megaterium and Bacillus ellenbachi from the silkworms.
  • Serratia marcescens (Metalnikov and Chorine, 1928),
  • Bacillus bombysepticus (Hartman, 1931),
  • Bacillus bombycoides (Paillot, 1942),
  • Streptococcus bombycis (Steinhaus, 1949),
  • Bacillus mucoides and Bacillus latrosporus (Steinhause, 1949),
  • Bacillus cereus var. alesti (Tourmanoff and Vago, 1950),
  • Aerobacter cloaceae and Achromabacter superficialis (Nakasuji and Kodama, 1969),
  • Streptococcus faecalis, Serratia piscatorium, Proteus vulgaris, Proteus inconstina, Proteus morganii, Proteus aerobacter, Proteus aerogenes, Micrococcus flavus (Kodama and Nakasuji 1969; Nakasuji and Kodama, 1969; 1970; Vago, 1963) were also reported to be pathogenic to silkworm causing flacherie.
  • Chitra et al., (1973) isolated Aerobacter cloacae, Achromobacter delmarvae and A. superficalis, Achromobacter delmarvae, Pseudomonas boreopolis, P. ovalis, Escherichia freundii and Staphylococcus albus.

References

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