Scientists use “genetic scissors” to find the first cure for the most common type of mushroom poisoning

Amanita phalloides doesn’t really look like much. But this inconspicuous mushroom, which also goes by death cap mushroom, is an absolute killer.

It causes around 90% of all human mushroom poisoning fatalities. It has killed, among others, a Roman Emperor, a pope, and a German King.

But now, this famously dangerous mushroom may have finally found its match: another seemingly inconspicuous substance called indocyanine green.

If you ever go mushroom foraging, this is probably the first mushroom you need to know and avoid. The death cap mushroom is primarily a European mushroom, but now, it’s fairly common on multiple continents. It’s also by far the most common cause of severe mushroom poisoning.

“Human mushroom poisoning occurs very often worldwide every year,” Professor Qiaoping Wang, Head of the Department of Pharmacology and Toxicology at Zhongshan University, tells ZME Science. “During the past 10 years, thousands of people got ill and several hundreds of people died from mistakenly eating toxic mushrooms.”

There’s also practically no antidote for the poison because, remarkably, we know very little about how the mushroom toxins kill cells.

The main toxin in the mushroom is called α-amanitin. When ingested, it typically causes irreparable liver or kidney damage. In China alone, there were 40,000 cases of severe poisoning in the past decade. Wang and colleagues used a genome-wide CRISPR screening to identify molecular targets for α-amanitin. The CRISPR tool, often described as “genetic scissors,” is a revolutionary discovery that enables researchers to edit genes very precisely, easily and quickly.

First, they used a cell line of human origin and created specific mutations within the cells. Then, they challenged these mutant cells with amanitin poison to see which ones fared better against the poison. Essentially, by figuring out how cells can withstand the toxicity, they can also figure out how to combat the poison.

“After bioinformatic analysis and we have found the genes and pathways that are responsible for amanitin cytotoxicity. Finally, we found the STT3B protein and its biological pathway is critical for toxin cytotoxicity. Then we confirmed these findings in liver cells and liver organoids since the liver is the target organ of mushroom toxins,” the researcher explained for ZME Science.

Armed with the knowledge, the researchers looked for ways to inhibit STT3B. They first started with FDA-approved molecules — if a drug that does this exists, why invent a new one? Lo and behold, they found a promising candidate in the virtual drug screening.

“We found 34 drugs that could be possibly STT3B inhibitors to block amanitin cytotoxicity.  After in vitro functional validation in cells, we only found indocyanine green (ICG) can effectively prevent cell death from amanitin toxin. Also, ICG blocked amanitin’s toxic effect on liver organoids,” Wang continues.

Indocyanine green is not exactly the first cure that would come to mind. In current practice, ICG is a dye useful in determining various bodily functions like cardiac output, hepatic function, liver and gastric blood flow, and for ophthalmic and cerebral angiography. But as it turns out, it also has another function — that of fighting amanitin poisoning.

“Finally, we tested the ICG treatment effect in mice,” Wang explained. “Mice were challenged with a certain amount of amanitin and ICG was given different hours later. The results demonstrated that ICG can prevent liver damage as well as kidney [damage] induced by amanitin. Importantly, ICG could improve survival after amanitin poisoning.”

Now, the researchers are doing two things. First, they’re continuing the research into exactly how STT3B is involved in amanitin toxicity. It seems that when the gene is inhibited or knocked out, it prevents amanitin from entering into cells — but it’s not clear just how it does this. Secondly, they’re planning on carrying out clinical trials to assess the effectiveness of the cure on humans.

While we don’t have results from clinical trials yet, this is definitely promising. For the first time, we have a viable candidate that could fight

The study was published in Nature.