Miracle drug

The miracle molecule that could treat brain injuries and boost your fading memory: discovered more than a decade ago, a remarkable compound shows promise in treating everything from Alzheimer’s to brain injuries: and it just might improve your cognitive abilities – Adam Piore/ MIT Technology Review – August 25, 2021.

If you stress a cell – and there are plenty of ways to stress a cell – one of which is for the cell to produce too many badly folded proteins – you are apt to shut down its production of proteins until the cell has got itself back together again. Or if that doesn’t work, the cell might just self-destruct.

Against which background, one scenario says that a lot of stressed brain cells means that the neural protein supply chains break down and that a lot of cognitive functions stop working. Perhaps stop the formation of new memories. Maybe damage old ones.

Hypothesis: that crippling cognitive problems seen in victims of traumatic brain injuries, people with Alzheimer’s, and even those born with the genetic problems implicated in Down syndrome are not caused directly by the diseases or genes or trauma but by the way cells respond to the resulting stress.

Then someone comes along with a magic bullet – aka an integrated stress response inhibitor (ISRIB) – which stops the stressed cells turning off protein production. Cognitive functions keep working.

A Google spin-off called Calico is working on just such a magic bullet. A company which has hired the inventor of the bullet, one Carmela Sidrauski.

While I worry – and no doubt they worry – about side effects. Is it really a good idea to turn off this basic safety mechanism? When all the red lights start flashing at Chernobyl, is it a good plan to press the manual override button? A more humble example is your car. When the red light for temperature lights up or when the yellow light for oil light up, you know you had better stop pretty soon if you don’t want to do a lot of damage to your engine – or worse.

So will all these re-enabled, stressed cells start doing all kinds of stuff which is not so clever at all?

But there is a more optimistic analogy from building a large computer system. When you start out you build in lots of alerts – that is to say the red lights – alerts to tell you when something is not quite right – perhaps the date on an in-bound birth certificate is not in the right range – and when you first start the system up, these alerts go off all the time, most of the time quite unnecessarily. But you work on the system and you work on the alerts and gradually you get to a position when the alerts only go off when they really have to, when there really is something that you have to fix. 

Maybe nature has been a bit rough and ready with its alerts in animals generally and there are going to be times with humans when that is not good enough. And maybe it will turn out that there are times when it would be reasonable just to turn them off. 

One catch here being that a cell does not have a intelligent supervisor looking on, looking in from the outside world in quite the way that a computer does, although in our multi-cellular case there is the host. And humans do have doctors. The cell does not have to be 100% self sufficient.

I suppose the people at Calico will just have to try the magic bullet and see what happens. Hopefully starting in a Petri dish than with a person.

References

Reference 1: https://www.calicolabs.com/. 

Reference 2: https://www.calicolabs.com/story/targeting-a-central-stress-pathway. 

Reference 3: Structurally Resolved Coarse-Grained Modeling of Motor Protein Dynamics - Holger Flechsig – 2011. Figure 1.1 above: Protein folding (schematic representation). Under the folding process, the macromolecular shape changes from a chain-like structure (left) to the compact, characteristic native protein structure (right) while crossing complicated intermediate shapes.