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Comment by ramraj07 | Hacker News Reader

When I was just starting out on my biotech undergrad I used to come up with whacky ideas every day after learning something new in biochemistry:

1. Rickettsia Bacteria have an ATP transporter! If we engineer E. Coli with this transporter, we can feed bioreactors with pure ATP and get even more efficiency! (Turns out this is not a real bottleneck in bioreactors, and you’ll likely waste more money synthesizing ATP anyway)

2. Glucose is transported in intestines via a glucose-sodium antiporter protein. Maybe we can find a drug that blocks this and you can eat as much sugar as you want! (Turns out you’ll have uncontrolled diarrhea if you do).

This idea sounds as boneheaded as these ideas. If there’s a “leak”, you bet your ass it’s there for a reason.

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> 2. Glucose is transported in intestines via a glucose-sodium antiporter protein. Maybe we can find a drug that blocks this and you can eat as much sugar as you want! (Turns out you’ll have uncontrolled diarrhea if you do).

It's very cool! It's the SGLT protein. It's actually a sodium-glucose co-transporter and is why gatorade is so effective! It's the perfect mix of salt, sugar, and water to take advantage of that very protein (where salt goes, water follows).

And yes there is a drug that targets these - it's the SGLT inhibitors and they're very in vogue right now. Ozempic and Mounjaro are the two big ones in the news right now. They act on the SGLT I (found only in the kidney) so that you urinate more sugar. They don't act on the SGLT 2 (only found in the gut) but other medications in that class act on both.

But congratulations and alas! You nearly invented gatorade and a multi-billion dollar diabetes and weight-loss drug. Hardly bone-headed ideas.

You got the meds wrong - semaglutide and trizapeptide are glp-1 based meds, sglt inhibitors are a separate class and don’t include those two - https://en.m.wikipedia.org/wiki/SGLT2_inhibitor

Importantly, the issue why my ideas were boneheaded was that typically there’s a lot of unknown side functions and ramifications in biology which are easily overlooked. Glp-1 based drugs weren’t discovered by deliberate hypothesis testing. Sglt2 inhibitors might be but given the number of trials it took in attacking metabolic syndrome using “logic” (avoid fat, avoid sugar, inhibit fat uptake, eat sugar substitutes, etc). This just eeems like a fluke more than merit of following simple logic into complex hormonal systems.

This is true in all medicines. Except antibiotics almost no effective medicine was “invented” by applying first principles the way you would in physics, even if initially it looked like that’s how it worked. Take chemotherapy for example. If the drug works effectively by killing all dividing cells completely, it clearly should kill you, but it doesn’t. It just kills cancers. But that’s because turns out our immune system plays a pivotal role in chemotherapy effectiveness.

Yes thank you. Midnight brain fart. It was Farxiga & Jardiance I was thinking of

> Glucose is transported in intestines via a glucose-sodium antiporter protein. Maybe we can find a drug that blocks this and you can eat as much sugar as you want! (Turns out you’ll have uncontrolled diarrhea if you do).

Uncontrolled diarrhea for how long?

I'd pay for a pill that would do similar to what you describe but for pizza instead of sugar if the uncontrolled diarrhea was only for a few hours.

So there’s one already - acarbose - it kinda blocks metabolizing starch and hence blocks its uptake. You don’t get diarrhea (that’s just because my idea tried to block the transporter which also transports sodium). But acarbose blocks starch metabolism so the bacteria in your tummy metabolize it and make you incredibly and unbearably flatulent. So not something you want to do if you have anyone else in your home lol.

> But acarbose blocks starch metabolism so the bacteria in your tummy metabolize it and make you incredibly and unbearably flatulent.

Sounds like a perfect product for a prank supply store.

Wasn't this the basis of the failed Olestra products? https://www.mentalfloss.com/article/619261/olestra-fat-free-...

Not exactly. It was an oil with large molecules.

It satisfied all the culinary requirements for being oil without being a lipid we could use, because it was too big to be absorbed. So it came through the tract as-is. Some people weren’t, er, oil-tight and experienced some seepage.

In the upthread scenario you’d be using something to block receptors so more real sugar can be absorbed but not metabolized. To your point, then it passes through, like the fake oil. But it’s because it has the assist from the blocker rather than itself being incompatible.

I’m a little surprised there’s an existing drug that does this though. I thought excess sugar heading through the kidneys was bad.

Don't sell yourself of biochem short though, you were an undergrad thinking outside the box. Sometimes we happen upon drugs by accident, but often someone went through the same type of train of thought as you and found an ingress into our biochemistry that could actually be exploited for a desirable outcome.

Ha ha I don’t, I thought I was on the right path, when I applied to Harvard for my PhD I sent them a copy of 30 such wacky ideas thinking this would convince them, but didn’t. I got rejected from every top 50 university first time (on top of good gpa, top GRE scores etc). Apparently publishing in your undergrad (which is pretty much something of pure luck in india) is the only currency they take into account. I still found my way to a good school and did my PhD though!

I also believe ideas are cheap and they probably do too, somehow that isn't paradoxical in my mind with my previous statement but I'm not sure if I could cogently explain why :)

I’m well past those days so don’t take it as a treatise on my own abilities but my experiences since have not suggested that these schools used any good metric in choosing students. They merely selected for the successful and hardworking folks. The latter trait is great but the former is not. If anything a phd is training for facing failure.

I also submitted subject GRE scores which in retrospect clearly differentiated people who will attain academic success and people who won’t. The universities literally said they won’t consider the scores even if submit them. Also, ideas are not cheap. Sure you have to execute on them as well, but ideas are not cheap at all. At least not the good ones.

There's a drug called Orlistat, which blocks absorption of fat from the gut.

The obvious side-effect is that your poo becomes very fatty and disgusting.

Hence the affectionate nickname for Orlistat in the biz: "Orlyshit" (i.e. Oily Shit)

> Maybe we can find a drug that blocks this and you can eat as much sugar as you want! (Turns out you’ll have uncontrolled diarrhea if you do).

Kind of similar to how olestra ‘may cause anal leakage’

>it’s there for a reason.

From the article,

>This leakiness could help plants protect themselves from damage from bright or rapidly changing light.

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