Details Matter

Seen during our last day on Maui. Evidently we missed the beheading? The prints in the sand suggest a dog was involved. We paused briefly, cringed, then moved on.

Back in Anchorage, at the dog park. If I recall correctly, I snapped a photo here sixteen years ago and made it the wallpaper on my lab computer, so I’d never forget how simply serene it is. It still is. Except the one big change we noticed since returning in 2009 is the number of trees felled by beavers, mostly near water’s edge, but also at certain spots around the lake quite a ways up the bank. And it’s not only trees, them beavers can wreak havoc on dogs caught swimming in the lake. Not so serene then.

Anchorage is opening up. The Goodthinkers at City Hall say the vaccinated among us may now move about nearly everywhere sans masks. And why not? Because the vaccine is 95% effective at preventing infection from Sars-CoV-2 (the details are important, keep reading), what difference does it make if there are cheaters among us, i.e. people who are not vaccinated and won’t wear a mask. That should concern other cheaters, but of course there’s a simple (and free) way for them to solve that problem, get vaccinated. That way you can sit right next to me at Suite 100 and enjoy a grilled fillet of Copper River King salmon over a garlic mash, with of medley of veggies, worry free. And if I’m feeling generous, I may even buy you your first glass of Cabernet, as a thank you for your contribution to herd mentality immunity. Win win.

I see signs around town advertising Covid-19 tests, the PCR kind!. Funny how the pandemic has established PCR in the modern lexicon. Even though most people will have no idea what it means (Polymerase Chain Reaction), how the test works, or any of that. Why should they? The technology most of us use day to day, we have no idea how it works. It takes me half a class period to explain to genetics students how PCR works. And they come to class with a basic understanding of DNA, if they’ve done their homework and attended lectures that is. But students aside, the average person doesn’t understand what DNA is, much less how it’s analyzed in a PCR test. All they need to know is that a negative PCR test for the virus avoids a ten day quarantine when they arrive in Hawaii. And who even cares how an exhaust emission test works, all I want is a Pass score on my car to fast-track it through registration, to avoid the dreaded visit to the DMV.

Imagine instead that before you could use a technology you had to prove you understood the basics of how it worked. Imagine the proof involved explaining to a child in the most basic of terms how a toaster works, how a combustion engine works, how a text message gets from one phone to another (it’s fascinatingly complicated). A close friend of mine once posited that if the average modern were sent back in time to the 17th century, well before the first chemical battery was invented, and had to explain to a renaissance scientist what a battery is and the basics of how it works, your average time-traveler would have no clue.

As a practical matter it makes no difference to most people how things work. If you want a crisp bagel you slide the two halves into the toaster slot, depress a handle, and wait. You don’t need to understand how a combustion engine works to drive a car, or how the “I love You” emoji gets to your wife’s phone, it just works, don’t ask me how. If you want to know the implementation details of how pretty much anything works in atomic detail, you need to educate yourself. This takes time – often a lot of time – and hard work. There are very few short cuts.

Most people don’t know (or even care enough to want to know) how Ibuprofen relieves pain, you just pop 800 mg into your mouth, wash it down with water and wait. For a long time I was one of those people. Then, in 2000, while living and working in Santa Fe, after having become disillusioned with the kind of work I was doing there, and had done for many years prior, along with the prodding of a close friend to break away from that to do something that interested me, I revisited my nerd-like interest in how drugs worked – and by interest I mean the actual implementation details of how they work, at the level of biochemistry.

Such learning takes time and commitment. And if I was going to do it, and succeeded, maybe I could parlay all that learning into a new career (though I didn’t give that part nearly enough thought). So off I went to get a PhD in Pharmacology, in the company of a woman soon to become my wife and two jug-headed dogs. None of them were too keen on leaving Alaska.

Fast-forward sixteen years. Have you ever thought about how THC makes you feel high (or for that matter what THC is)? I think I know now! Or even wondered more deeply about alcohol? Like why does the addition of a single carbon atom to methanol (C-OH), itself a very lethal compound, create a new alcohol called ethanol (C-C-OH), which doesn’t kill you, but instead merely makes you drunk (notwithstanding lethal doses, relatively rare among drinkers). Add another carbon and you get propanol, similar to ethanol in how it effects humans, but much more potent and more likely to be lethal. Add still more carbons to the chain, or change the order of how atoms connect (who knew stereo-chemistry was so important!), and the alcohol’s properties get even more weird.

Ever wonder why drugs have so many side effects? Some can be severe. For example, listen to the mellifluous voice on any TV ad pitching a new drug (call it, Euphorimab) – “Euphorimab may cause stroke, internal bleeding, or complete loss of appetite. If you lose consciousness or die after taking Euphorimab, please notify your doctor immediately.” Ha ha, funny, right? But all kidding aside, do side effects occur because drug company scientists don’t really know how the drug works, the implementation details? No. The bar for approval of a drug is actually pretty high, usually including proof of the molecular mechanism of action of the drug. There are exceptions*. Before a drug is approved scientists must provide considerable experimental evidence that shows Drug X modulates (inhibits or activates) a specific protein known to be causative in whatever malady it was designed to alleviate. But there remain two big challenges in drug development 1) Many of these “target” proteins occur in different parts (tissues) of the body, and 2) many drugs are promiscuous, in the sense that they have unexpected, off-target activities in the body. Meaning the drug can bind to and modulate proteins it wasn’t designed to target.

* A class of drugs known as volatile anesthetics are a notable exception to the rule. They’ve been used to anesthetize patients starting 160 years ago, before the FDA took on its regulatory approval function. They’re still approved for use in patients undergoing surgery even though nobody knows how they work at the molecular level. You’d probably get a Nobel prize if you could figure it out. I once rotated in the lab of an anesthesiologist (and pretty good geneticist) who was trying to figure it out. We never did figure it out but we killed a lot of worms trying.

Example: Vicodin is (or was) a widely prescribed narcotic active in the central nervous system to alleviate musculoskeletal pain. But for a lot of people it also makes them very drowsy, nauseous, and constipated, some severely. Mood swings and poor judgement are not uncommon side effects.

Scientists are pretty certain Vicodin works by binding to and modulating a class of proteins called mu-opioid receptors. Activating these receptors in the central nervous system has the downstream effect of inhibiting the brain’s pain response circuit, but at the same time activating certain reward pathways in the brain (the reason for opiate addiction). But these receptors occur in other places in the body too; one of which is – believe it or not – the gut. The gut doesn’t do the thinking or pain processing in the body, that’s the brain’s job, so what are these receptor proteins doing expressed in the gut? Answer: it’s all about context. Tickling mu-opiod receptors in the gut (versus the brain) with a dose of Vicodin triggers them to “signal” back to the brain, via the nervous system, that something is out of whack down here. That in turn generates another cascade of effects, also mediated by the nervous system, which end in the feeling of nausea in the gut, and often a backup of poop. So, generally speaking, depending on which tissue a protein is expressed in, different (unintended) side effects may occur after a drug binds to it.

The other cause of side effects, drug promiscuity (so-called “dirty drugs”), is much harder to deal with. As mentioned, drug approval usually requires experiments to prove how a drug works at the molecular level, and in turn how that will reduce disease (or pain, etc.). But selective experiments can’t detect if the drug is also active against other protein targets. It’s only after the drugs get into real patients that the side effects of “off-target activities” are discovered, and the corresponding proteins/pathways identified (sometimes). Certain chemotherapy drugs, for instance, are notorious for off-target effects – hair loss, severe fatigue, constipation, vomiting, weight loss, bleeding, muscle & joint pain, etc. (Can you hear that voice on the TV ad?).

Wait, don’t we have precision medicine now? Can’t you design a drug that targets only a single protein? Yes, but it’s damn difficult. Gleevec is the best example I can think of. It’s used to treat certain types of leukemia. It was designed to target a mutant protein (oncogene) produced in patients with a specific chromosomal aberration. It took many scientists working many years to characterize the molecular details of this aberration, and then more years to design a specific drug to target it. Think about how difficult it would be, and how long it would take you, to make a key for a lock you can’t see with the naked eye, and can only model (in 3-D) using indirect experimental evidence.

OK, I’m rambling. The point is, drugs are really just another kind of technology. And, like most other technologies one people don’t need to understand the details of in order to benefit from. Coming to know the details, on the other hand, if you’re curious like I was, will convince you just how freakin’ complicated biology really is.

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