The secret behind the poison in a fish considered a delicacy
Plus a drug for one of cancer's toughest targets, a new pill for COVID-19, a silent killer, potty-trained cows, human origins, and algal blooms from wildfires.
Pufferfish (fugu) is a delicacy in Japan. But it has to be prepared carefully since some species accumulate a deadly poison in their livers.
The compound in pufferfish (tetrodotoxin) is about 100 times as toxic by weight as potassium cyanide. Around 2 mg can kill an adult.
It’s even made it into an excellent episode of the detective show, Columbo.
The crazy thing is that pufferfish don't actually make tetrodotoxin themselves. Rather, it is made by bacteria that live inside the fish. In fact, the same deadly toxin is also found in certain frogs, blue-ringed octopus, floral egg crab, and basket shell snails.
It gets more interesting. You can grow pufferfish with filtered water that doesn't contain the toxin-producing bacteria and they grow just fine. Presumably they taste just as delicious. In the wild, the pufferfish take up the bacteria that make tetrodotoxin to prevent being eaten!
Tetrodotoxin is toxic because it blocks channels that control the movement of sodium ions across nerve and muscle cell membranes. All animals have them, which begs the question- how do pufferfish accumulate this toxic compound without dying themselves?
Mutations! Pufferfish have evolved to have different versions of these sodium ion channels encoded by eight separate genes. In effect, they are resistant to the toxin.
A drug for one of cancer’s toughest targets.
This week’s column for Hindustan Times (which you can read here) did come from a very basic question—
How does a tiny pill work after you swallow it?
In a leap of faith, millions of people pop pills daily without asking how they work. What exactly is a drug? How does it work? How is it discovered? Why are some drug targets “undruggable”?
There are over 20,000 protein-coding genes in the human genome. Only around 2%, or 500, are targets of drugs. Is most of the genome truly “undruggable”? There are some incredibly recalcitrant proteins in deadly cancers, but some of them are finally being targeted by drugs.
For three decades, KRAS was considered “undruggable”. Mutants of the protein are found in types of lung, pancreatic, and colorectal cancers. These are dreadful diseases. My grandmother and an uncle succumbed to them.
KRAS is important because healthy cells need this protein. And the surface is like a Borg spaceship from “Star Trek”— there’s no place for a drug to enter. The trick was to identify a mutant that had a “sticky” amino acid and a small transient gap a drug can creep in to.
In May. the first KRAS inhibitor was fast-tracked FDA approval for lung cancer. Now, it’s also been shown to work for colon cancer as part of a combination therapy.
Silent but deadly.
Imagine waking up late one morning, not being able to speak or breathe, and finding that half your family and half your villagers had died in the middle of the night of unknown causes.
This is not a fictional story. On August 21, 1986, around 1700 people never woke up.
For a while, the cause was unknown.
Lake Nyos in a remote part of Cameroon is one of a handful of known exploding lakes. When a limnic eruption occurred, this lake emitted a cloud of carbon dioxide that suffocated thousand of people and livestock.
A pill for COVID-19 might come before the end of the year.
We really need a drug in pill form that works for COVID-19.
Molnupiravir is in late phase clinical trials and may be approved by year-end. How does it work? Here's a great perspective just published on its mode of action (called error catastrophe).
Here's the key observation: Molnupiravir gets embedded into viral RNA as it is getting copied, and the “copier” makes a ton of mistakes. And the drug seems to be generally variant-resistant at the time.
What else I’ve read:
Potty-trained cattle could help reduce pollution.
Accurate protein production promotes longevity.
Australian bushfires triggered Southern Ocean algal blooms bigger than Australia
On human origins. This is one of the best long-reads of the year.
I have seen people queueing up for this deadly fish at restaurants in Tokyo! I admire their courage!
I have seen people queueing up at restaurants for this deadly fish!