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- A Thousand Worms: Marine invertebrate substance relieves pain better than opiates
A Thousand Worms: Marine invertebrate substance relieves pain better than opiates
Russian scientists have proposed a method for the industrial production of tetrodotoxin from marine worms. It is one of the strongest known toxins, most commonly known as puffer fish venom. An analgesic based on it can last up to two weeks. According to experts, 1 g of tetrodotoxin costs about $100,000 on the world market, since it requires processing about a ton of fish. At the same time, a similar amount of the substance can be extracted from just 360 g of invertebrate biomass discovered by the researchers. According to experts, the proposed technology really brings closer the possibility of mass use of a powerful analgesic, which is not addictive. However, according to them, it may take years before the clinical use of such a drug.
The most valuable poison of the puffer fish
Specialists from the A.V. Zhirmunsky National Scientific Center for Marine Biology of the Far Eastern Branch of the Russian Academy of Sciences have discovered and studied a type of marine worms suitable for the industrial production of tetrodotoxin (TTX). This is one of the most powerful natural toxins: it is about 10 thousand times more toxic. It is several times superior to potassium cyanide and is widely known as the poison contained in puffer fish. The substance blocks the transmission of nerve impulses, so it can be used as an effective painkiller. However, obtaining the substance on an industrial scale has long remained a difficult task. To produce 1 g of TTX, the cost of which reaches $ 100 thousand on the world market, requires the processing of about a ton of fish. At the same time, a similar amount of toxin can be obtained from the eggs of about 2.4 thousand individuals of nemertine worms — this is about 360 g of biomass.
— There is a serious problem with painkillers today. In fact, morphine remains the only truly effective remedy, while other analgesics have to be used in significantly higher doses. At the same time, there are substances in nature that can block certain channels in the nervous system, providing an analgesic effect lasting up to two weeks. Tetrodotoxin also belongs to such compounds," said Timur Magarlamov, senior researcher at the A.V. Zhirmunsky National Scientific Center for Marine Biology of the Far Eastern Branch of the Russian Academy of Sciences.
According to the researchers, the international TTX market in 2022 amounted to $710 million. Its high cost is explained by the complexity of production. The chemical synthesis of the toxin requires a large amount of feedstock with a maximum final product yield of only 11%. And the extraction of venom from the liver of puffer fish requires the capture of many individuals, which damages the population.
In 2024, scientists went on an expedition to Cape Anastasia on Sakhalin Island, where they collected several hundred individuals of the species Cephalothrix mokievskii. Laboratory studies have already shown that these marine worms contain high concentrations of tetrodotoxin and can be compared to puffer fish in terms of toxicity. Nemertine females have the highest toxicity, and their eggs contain the largest amount of venom.
— During the spawning period, one female is able to produce a pool of eggs containing up to 420 micrograms of TTX. It is important to note that C. mokievskii nematodes are unpretentious to the conditions of their detention and are capable of spawning several times a year, which makes it possible to consider their eggs as a potential renewable source of TTX," the scientist said.
In the course of further research, the specialists selected the most suitable conditions for the long-term maintenance of female nemertines in captivity, determined their toxicity and "forced" them to produce TTX-containing eggs in artificial conditions. Experiments have shown that in the absence of poison in the diet, nemertines retain it both in their own tissues and in their eggs.
Practical application of the substance
However, further research is needed to complete the development of a sustainable nemertine cultivation technology. So far, scientists have only a limited sample of individuals for research. The physiology of the species, the sources of the toxin, and the environmental factors that determine its accumulation in natural conditions have also not been sufficiently studied. In addition, the regular selection of a large number of individuals from natural populations can have a negative impact on their numbers. Therefore, it is important to develop a method for cultivating C. mokievskii in the laboratory at all stages from stimulating spawning and obtaining larvae to the formation of juveniles with monitoring of the dynamics of TTX accumulation.
As immunologist Mikhail Bolkov explained to Izvestia, modern biotechnologies even make it possible to embed various genes into organisms so that they secrete the necessary product with the necessary properties. Therefore, the industrial production of tetrodotoxin from worms seems logical.
— For a long time, opioids were considered the most powerful analgesics, but with their chronic use, a certain part of patients develop dependence. If it is possible to create a new painkiller — an alternative to nonsteroidal anti—inflammatory drugs such as ibuprofen, as well as addictive drugs — this will become an extremely sought-after and significant invention," he noted.
The idea of obtaining tetrodotoxin not from the liver of puffer fish, but from the eggs of super-toxic nemertines looks technologically and environmentally sound, but the project is still at the level of experimental technology. It is necessary to prove the stability of the yield, develop a method of cultivation on a large scale, as well as regulate the purification and quality control of the substance, says Maxim Kolyasnikov, associate professor at the UrFU Institute of Economics and Management and the Department of Future Technologies at MIPT.
— The key commercial risk is that without understanding the source of the toxin, the factors of its accumulation in captivity and the composition of the microbiota, it is difficult to guarantee the same concentration and profile of impurities from batch to batch. In the near future, the market for standardized reagents for neuro- and microphysiology is the most realistic. For medicinal use as an alternative to opioid analgesics, it will take years of pre—clinic and clinic," he said.
In addition, tetrodotoxin has serious competitors in modern conditions. In practice, complex analgesic therapy is increasingly used, which involves a milder effect on the body. For Russia, such a development is primarily promising from the point of view of import substitution, whereas entry into world markets is possible only in stages — after confirming the effectiveness of the methodology, its successful scaling and passing all export restrictions applicable to highly toxic substances, the scientist concluded.
Переведено сервисом «Яндекс Переводчик»
