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I feel much better, dare I say fully recovered. There is no trace of the horrible hives visible anywhere on my skin. My hands and forearms occasionally still itch, weird given there’s no evidence of a rash or reddish skin. Truly, I thank all of you who wrote or called to inquire how I was coming along, and to wish me well. Life at 61.2° north latitude can make one feel a bit isolated, especially now on the eve of the annual Endarkenment. Bless you all.

November 9th: This is Kincaid Bluff where I often walk with Black Dog. A place where owls and eagles sometimes come to hunt, and a great place to be alone with your thoughts. During the week there are very few people here. If you’re not careful, though, as one walks about the mind can get caught up in what seems like an infinite loop of self rumination. When that happens to me I know it’s because I’ve slacked off on my meditation practice.

Eleven days later in downtown Anchorage outside a restaurant where HW and I stopped for a drink. By then it had turned unseasonably cold, evidenced by a clear night sky, rising smoke and condensed water vapor. The west wind that night didn’t help either (note the three flags – American, British, & Alaskan).

Wait, the Union Jack? Yes, that’s the Captain Cook hotel. Some British based company still holds an ownership interest (iirc). There’s also a statue of Captain James Cook near the hotel, erected on the bluff overlooking Cook Inlet. Rather than revere him, certain folks want to cancel him. I’m of two minds about this. Actually, three. One, I’m not big on statues to begin with. It seems to me there are better ways to commemorate the life of an individual who has done good things for society other than erecting a massive metal likeness in the public space. Especially where controversy exists over whether the person is really good or not, like someone more deserving of an anonymous grave than a memorial (looking at you Saddam). Two, back to Captain Cook, he was unquestionably an intrepid explorer (cancelers would counter exploiter) sailing about the globe checking off a number of firsts for global navigation and the Royal Navy. He deserves a bit more than a hat tip for that if you ask me. But (thirdly), he wasn’t exactly Mother Theresa in every encounter with indigenous people, and I get that, but it seems to me too often cancelers cherry-pick their objections where they feel culturally aggressed. Heck, you can even find people who don’t believe Mother Theresa was the saint the Pope declared her to be.

Wine Turkey Friends, in case you’re wondering

And then Thanksgiving arrived. Our friends and hosts (left) had us out to their house on the lake, an hour drive north of Anchorage. We all imbibed generously and packed our pie holes with prime rib, smoked turkey, salads and sides galore. For desert, we plied our pie holes with pie. The hives would start three days later, not caused by anything to do with Thanksgiving, of course.

It’s become a custom of ours at Thanksgiving to go around the table and have each person offer one thing s/he is thankful for. When it came to me I said, sincerely, I was thankful for the Covid vaccines. If not for the vaccine then Thanksgiving with friends, and other gatherings throughout the year, may not have been possible out of an abundance of caution.

…

If that thing I was thankful for surprises you, if it seems inconsistent somehow with my worldview of things or political tribalism, then allow me to disabuse you of that misconception right here.

By now there is so much accumulated misinformation about the Covid vaccines, mostly the mRNA variety, that trying to correct an individual’s mistaken beliefs is like a game of Whac-A-Mol. “They’re unsafe, they’ve never been approved by the FDA!” or “Nobody really understands what’s in those shots, I ain’t puttin’ that shit in my body!” or “Don’t do it, it will alter your genome!” or “The shot is pointless – you can still get Covid!” or “It’s a conspiracy by the Democrats to control us, they want to take away our freedoms!” Or or or… you get the idea.

Let’s talk about the science. Actually, I already got started on that here, a summary of what I found to be an interesting feature of the mRNA technology around the time the vaccines were first approved by the government under an emergency use authorization (EUA). Does EUA mean the government bypassed the usual rigor of FDA clinical trials (Phases I-III) that ordinarily must be passed to finally approve a drug (vaccines included) for use in humans? Yes, technically speaking, that entire formal process was bypassed for the mRNA vaccines. However, what is emphatically not true is the nonsense that no testing was done in real humans before the EUA. Over 30,000 people were enrolled in a trial to assess the efficacy of the Moderna mRNA vaccine, and 40,000+ volunteers were enrolled in a separate trial for the Pfizer vaccine. Roughly half the people in each trial were given the vaccine, the other half placebo. They were followed for a time and the results published (Moderna, Pfizer) in a highly respected scientific journal. The efficacy in both trials was astoundingly good (>90%) at preventing Covid-19. Specifically, against the founder variant of SARS-CoV-2, but later both vaccines proved highly efficacious against the Delta variant as well. In the end, over 35,000 real adult humans received 2 doses of an mRNA vaccine and not a one of them grew a third eye or suffered any near term pathology. None of them died. Most of them, however, avoided getting infected by the virus and sick with Covid-19. Infections and illness in the placebo group were, of course, significantly higher.

For skeptics who might still complain this “experiment” was too small to merit rapid approval, I have to wonder, how on earth would they know? How can it be so many people, who before Covid couldn’t tell you a single fact about what ingredients are in a given drug, never mind how its safety and efficacy were assessed, suddenly become experts in assessing the results and experimental design related to the mRNA vaccines? This is especially suspicious in light of the long-standing harsh criticism of the FDA that, if anything, the drug approval process in this country has been – and continues to be – far too slow. Thus delaying (or preventing) potentially life-saving (-extending) therapies to Americans suffering from major illnesses. But now, suddenly, some of these same people are suspicious that a highly efficacious vaccine to prevent death by infection from a virus, was hurried? Sorry, that trips my BS detector. I would bet you that any person who advises against getting a vaccine shot merely because it is “experimental,” had this person failed standard treatment for his cancer and was offered an unapproved, experimental drug that might save his life or delay dying from it, would jump to volunteer for that trial! But a vaccine against a virus that’s killed hundreds of thousands, that by now has been safely injected into tens of millions of people’s arms – well, one can’t be too careful you know 🙄

I intend no disrespect by that. It’s just that for people who are ordinarily rational and clear-minded, to lapse into this kind of epistemic brain fog…I dunno, I just don’t understand it. The only explanation that makes any sense to me is they’ve been swindled by pseudo-scientific grifters on the Internet.

Another thing: mRNA. Prior to 2020, ask your average person what mRNA is and you’d be met with a blank stare. Or ask ’em how a chemical car battery works. “What?” Point is, your average person (me included) doesn’t understand even the basic principles of many of the technologies we benefit from. I’ve talked about this before. And, as I concluded in that piece, it’s no different for drugs, which are a kind of technology. Except when it comes to drug technology I personally do know more about how the technology works (including the mRNA vaccines) than the average person does. So it peeves me to no end when I hear people’s vaccine hesitancy is based on misinformation – nay, complete nonsense.

I recently gave a short presentation to co-workers on this very topic, and for the same reason, to reduce any vaccine hesitancy among them and/or their friends and family. This is from the last slide in my deck

Focus on the first step (left) – DNA –> RNA –> Protein. It shows how protein is made, naturally, in every cell in your body. Unless you’ve had a class in molecular or cellular biology you likely would not know that mRNA (messenger RiboNucleic Acid) has been known since the discovery of the DNA structure by Watson & Crick to be the intermediate molecule whose sequence specifies the precise kind of protein to make. Far from being a toxic or scary substance, mRNA is in fact 100% natural! Every single cell in your body is constantly making new mRNAs for the ribosome to translate into protein. If that didn’t work, you’d soon die, or worse, you’d never have been born.

Fact #2: The Sars-CoV-2 virus is itself an mRNA virus! When it infects your cell it spills its contents (mRNA + other stuff) and hijacks the ribosomes in the cell to translate its own proteins (including the so-called Spike protein). This is the way it makes more copies of itself, and eventually makes you sick. The genius of the mRNA vaccines is this: We’re fighting fire with fire – brilliant! This is because the active ingredient in the vaccine (mRNA!) codes for just the Spike protein. Once inside your cells the vaccine mRNA is translated into viral Spike proteins. Once those proteins are booted out of the cell they train your (adaptive) immune system to be recognized as foreign. So that if you subsequently get infected with the virus it will be targeted and destroyed by the immune system. The only other stuff in the vaccine formula is a little sugar and fat to stabilize the mRNA so it can get into your cells to develop immunity. That’s it, nothing super different, chemically speaking, than what you’d find in a Starbucks latte.

“But wait – I heard the mRNA can alter my genome!”

No, false. Generally speaking, neither the mRNA in the virus nor the vaccine can be converted back into DNA inside your cells. It’s possible to achieve experimentally, but suffice it to say it doesn’t happen in this context. Advanced topic that.

“But you had a nasty adverse reaction to the Moderna booster shot, didn’t that cause hesitancy in you?”

No. I’m evidently in a minority of people who experienced a bad reaction, an overstimulated immune response, I believe. As I’ve mentioned before on this blog, biology is hard, very hard, and drugs have side effects, which can be variable across individuals who take them. But the benefit of vaccination against Covid clearly outweighs the chance of an adverse reaction. The latter being something I can (and did) endure, the former may kill me. If your calculus is different, if you don’t think Covid will kill you, fine, don’t get vaccinated to protect yourself, do it for your family and friends and others in your social sphere, to reduce the chance of spreading it to them if you do get infected. Don’t not do it because the Democrats urge you to, or because Joe Biden wants you to, or CNN implores you to; do do it because it’s the rationally correct choice to prevent yourself and others from getting sick and possibly dying. Otherwise, self-isolate. Those are the only rational options as I see it.

Still hesitant? Consider the above photo: One of eight (!) aisles at our local Natural Pantry store packed with over-the-counter pills, potions and tinctures for whatever ails you. What do you wanna bet “The Cleaner” (foreground) is nearly sold out because some debunked, quackpot ophthalmologist in Oklahoma convinced tRump it works as well as a swig of household disinfectant to kill the virus. 🙄 Point is, lots of people exhibit no hesitancy to waste their money on this crap, the lot of which has zero credible evidence of efficacy in any pathology they intend to treat. Yet many of these same people are deeply wary of a vaccine proven, in real human beings, to prevent getting severely sick and dying from a virus. Go figure.

“They mostly come at night…mostly.”

-Newt (Alien the movie)

I suffered (and still am) a severe outbreak of hives. First time in my life. They erupted suddenly in the wee hours of the morning eleven days after receiving a booster of the Moderna vaccine. We ruled out allergens as a cause, such as food, exposure to weird animals, travel-related interactions, laundry soap & dryer sheets, etc. And I’ve never had an allergy to anything in my life. So nothing made sense as the cause except the booster. But eleven days delayed? I was dubious. Then I started reading around. Sure enough, I’m not alone.

Spent the better part of the last four days since the onset of symptoms researching disease pathways in Chronic Spontaneous Urticaria (aka Hives). The chronic form of hives refers to a condition lasting more than six weeks, less than that and it’s classified as acute. I’d like to think this crap will resolve before six weeks, but everything I’m reading where the vaccine was the likely cause indicates maybe not.

Thing is, my particular brand of this misery, since it was not caused by an allergic reaction to food or medicine or what have you, is classified as “etiology unknown”, doctor speak for we don’t know what the cause of your type of hives is, Rod. As I said, I’m quiet certain the cause was the vaccine but I don’t think it was an allergic reaction to anything in the vaccine formula (e.g. Polythelene Glycol (PEG)). If so I would have had this problem after the first or second shot earlier this year, and I didn’t. Rather, somehow the booster shot over-activated an immune response pathway in me (and apparently in roughly 1% of all vaccine getters), presenting similar to what is seen in an allergic response, but through a different biological pathway. If this turns out to be a chronic form of hives there’s not much information on how long beyond six weeks the hives might last and what treatments work best to deal with the symptoms. The worse symptom, as any hives sufferer will tell you, is the inability to fall asleep and stay asleep. This is because the hives come out at night and are intensely itchy. During the day the itchiness is way down, and scratching more easily resisted. Creams, ice, and antihistamines all help inhibit the itchiness and hive production but they don’t stop it entirely. Something about trying to fall asleep in a supine position in a warm bed makes it worse. Standing or sitting and focusing the attention makes the itchiness fade away I’ve found. Steroids (e.g. prednisone) suppress the immune system and they have helped tone mine down and curtail hive production, but hard to say how much.

This unfortunate experience hasn’t turned me into an anti-vaxxer, although to be completely honest, had I known this would happen I would not have gotten a booster. There are other ways to protect yourself from getting infected with the virus and getting sick with COVID, like staying home and going out only when necessary. Not ideal, but practically speaking HW and I are now able to do that.

And now if you don’t mind I’m off to try and get some sleep. Not optimistic.

Redemption? No, a bad look. Very bad. Our Cerebral Man by day, widely revered quarterback by night, having been given an open mic proposed to set the record straight, to dispel the lies and disinformation spewed from our public podiums (Flitter, Faceplant, Instachat, Snapgram, what have you). These untruths about me, he began, were pervaded by… wait for it… of course, The Woke Mob!

By this time I’d straightened in my chair, made the video full screen, turned up the volume as high as she’d go. What’s this? I leaned in, not wanting to miss a word.

A little background first…

You remember the game show Jeopardy, where a contestant chooses a category and then Alex Trebeck (R.I.P.) reads an answer to a question in that category. The first contestant to click their buzzer gets to “answer” with the corresponding question. Get the question right, and the contestant is awarded the points for the answer. For example: “Alex, I’ll take ‘Famous Misleading Statements‘ for $400, please.”

Trebeck: “I’ve been immunized.“
Contestant: “What was Aaron Rodger’s reply to the question, ‘Have you been vaccinated’?“

Correct for 400 points!

Now, imagine the subject, a candidate replacement for Trebeck no less, would have us believe that the contestant’s response in fact would have been incorrect. The correct question to the answer, he’d have us believe, would’ve been: “What was Aaron Rodger’s reply to keep the Woke Mob off his back.”

Nope, that’s wrong. Deliberately misleading people is wrong. C’mon, we’re talking an ethic any sixth grader understands. Woke Mob, puhleez 🙄 . What you did (said) at that presser back in August, Mr. Rodgers, is called deflection. You said it to exempt yourself from the inconvenient protocols the NFL player’s union – of which you are a member! – agreed players would have to abide. At least one of which you personally judge, unscientific. That last would be easily dismissed as merely amusing if not for the fact that you want your fandom to understand you as a “critical thinker.” (Never mind those crackpot conclusions from your own personal research 🙄 ).

No, Mr. Rodgers, you misled (lied) because you didn’t want to have to follow the rules other players – fellow members of the player’s union – had to follow after they acknowledged, truthfully, they are not vaccinated. You evidently think you’re special somehow, not all rules apply to you.

And to think you almost got away with the deception, if not for getting infected with the virus.

Your critics are right, you gave evidence you’re untrustworthy. Stop sniveling and Own It.

Let’s kick this post off with a little coffee porn. Meet Guissepe!

We still name things in and around the home, animate and not. Our former machine, Geppetto, after fourteen years of dutiful service has moved on to a new home, that of a recent house-sitter who I came to learn loves espresso. She was once a barista herself. Guissepe is a dual-boiler machine with a pre-infusion chamber, ideal for lightly wetting the coffee “puck” before the push of pressurized steam. This improves the flavor profile of the shot. Can you tell I’m a purist ;-). He’s also programmable, allowing you to automate the precise temperature and volume of every shot (double or single). I rarely pull singles for myself or HW (she enjoys milk-based drinks) but it’s a nice-to-have for the occasional guest whose caffeine tolerance is lower than mine. The steam wand is a four-hole jobber, so creating silky micro foam for lattes and cappuccinos is a breeze, once you get the hang of it.

There are many factors at play in an exceptional shot of espresso. It starts with the beans, of course. (Pro tip: Did you know the coffee bean is the nut of the fruit of a coffee plant (or tree), which is classified as a cherry). The type of roast one prefers is subjective. There are many good beans to choose from. I tried this one recently, a medium roast, and it was very good. Regardless of the roast you prefer, the beans must be fresh. Opinions differ on what “fresh” means in this context. My opinion is roasted beans, properly kept (air-tight container in the dark) should be consumed within 4-5 weeks of the roast date. Much beyond that and something happens to the beans causing the flavor to decay. The cause of this (chemistry) interests me though I don’t yet understand it.

Next comes grind. This is hugely important. For espresso, you must purchase a quality burr grinder. Do not even think about trying to make quality espresso using a conventional coffee grinder, it simply cannot grind the coffee fine enough. Burr grinders are not cheap. Ours is a Mazzer mini (aka Massimo, photo: left of Guissepe) that we’ve had for over fifteen years now. It’s a continuously adjustable model allowing you to dial in the grind just right. Which is what? Well, like everything else, it depends – mostly on the roast color (light, medium, or dark), the freshness (believe it or not, fresh vs old beans can render very different coarseness on the same grinder setting), and even bean size. Once you account for all that your goal is ground coffee that has the consistency of finely granulated sugar. Compared to the coarsely ground coffee you’d use in a drip machine, a fine espresso grind maximizes the surface area of the coffee exposed to the infused water, which extracts the flavor into the shot.

Then there’s the volume of ground coffee in the basket. Experts recommend about 16-18 grams (for a double), adjustable depending on the size of the basket of course. Most “prosumer” machines, like Guissepe, have baskets large enough for that dose. Next comes the tamp. You need to invest in a good tamper, and like every gadget in making good espresso there are many to choose from. My advice: stick with the old-school style tamper, like this one. The rule-of-thumb is to tamp (compress) the evenly-distributed (!) grounds in the basket to about 30lbs of pressure. Although experiments I’ve seen concluded no difference in the final shot quality over the range of 5-30 lb. tamps. My advice: experiment til you get it right.

So, you’ve nailed the proper grind, decanted 16 grams into the basket, and tamped appropriately. That’s the puck. The next factors are water temperature and the bars of pressure needed to force hot water through the puck. I like 94 degrees centigrade for temperature at the brew head. As noted above, this value is programmable on Guissepe; the pressure on the other hand is a readout, displayed on the manometer (see photo). As the shot is being pulled the dial shows the pressure at the brew head. Again, depending on the volume of coffee, the grind, and the tamp, this should be around 7.5-9 bars of pressure. Below that minimum and the grind likely is too coarse; above, too fine.

Some machines don’t have a programmable volume feature. On those, another factor in drawing an a exceptional shot is how long to let the steamed water infuse the grounds. Opinions vary, but the rule-of-thumb for beginners is about 25-30 seconds (including pre-infusion if you have it). Guisspe has this feature but I still pay attention to the shot time. For a double, if it’s well outside this range I change my upstream parameters (finer/coarser grind, coffee volume, tamp strength, etc.).

And that’s it – time to enjoy! If you’ve dialed in all the parameters that go into an exceptional shot of espresso it should look something like this

Aficionados will note the quality of the crema there, that exquisite caramel cap on a perfect shot. If it’s too thin (or “blonde”) the coffee was likely over-extracted, and probably bitter; too thick and oily, under extracted, possibly sour.

At my workstation, during an average day, for myself and HW I will pull a total of four, sometimes five, double shots. At day’s end I clean up my mess, wash dishes, refill the reservoir (2.4L) and shut him down. I do that on my phone now since I connected Guissepe to a smart switch, which also lets me turn him on in the morning to heat up, without getting out of bed. First-world living!

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What’s your worldview regarding the goings-on in Afghanistan, especially the evacuation?

Tragically, it looks like the last really bad mistake of nineteen years of mistakes. Not twenty years, because to be fair I think the original casus belli in 2001 – the Taliban giving safe harbor to Al Qaeda – was a reason (it could be justified) to bring American hellfire to bear (sorry, “coalition” hellfire). But after that mission was accomplished, the inexorable segue into nation building (something Bush, you’ll recall, thumped was not going to happen in Afghanistan!) was a fools errand. But what should we expect by now from American military adventurism? Except for Bush, Cheney, Rumsfeld and Rice, I doubt anyone else thought that ramping up a military presence in Afghanistan to keep the Taliban at bay, rebuild infrastructure, improve the lives of women and children, and train Afghans to provide for their own security (American-style), was going to end well. It certainly didn’t help that nearly every year since 2001, when military commanders updated the senate foreign relations committee – “Hey, how’s it going over there, are we still winning hearts & minds?” – they replied, “Yes.” In so many words, anyway. So yeah, the evacuation, operationally speaking, is not a good look. But that in itself shouldn’t come as a surprise, because the American public has been misled for years about how things are going over there. That, or not paying attention. I mean, seriously, what do people expect the evacuation should look like, the orderly boarding of a flight from LA to Miami? War is hell, remember? Even in the wrap-up phase, evidently.

What’s the explanation for the unexpectedly rapid takeover by the Taliban?

Unexpected by whom? I doubt this was unexpected by the Taliban, or most citizens of Afghanistan, or that feckless former president, Ghani, or even the Pakistani government who has been giving support to the Taliban in one form or another for years. (BTW, that last is a dirty little secret most Americans have not been told). So no, I don’t see it as unexpected. The other thing many Americans don’t appreciate is that the Taliban likely became better fighters by every measure simply as a result of being hunted and killed by the American (sorry, “coalition”) forces for twenty years. In a nutshell, we forced them to get better. Another reason it was so fast is that it appears the Afghan government forces, the ones we spent twenty years propping up and training, put down their arms and walked away in return for assurances from the Taliban that they (and their families) would not be killed after the takeover. Other reports I’ve read indicate that many (how many is unclear) Afghan forces were never loyal to the government forces in the first place. In fact, many were known to be Taliban sympathizers, if not wannabes.

Are you sympathetic toward the special fears women in Afghanistan have now that the Taliban have regained control?

Yes, without reservation. There’s no evidence the Taliban leadership, however constituted, will begin to play nice and show respect for human rights, women’s in particular; these men are under the spell of a Dark Ages form of religion. But whenever faced with a question like this, my thinking usually turns to how the mess could have been avoided in the first place. Alas, I don’t have a good answer for that. The tragic fate of many women and girls under the truncheon of Sharia Law predates the start of the war in Afghanistan. This brand of barbarism has been in place for a very long time. What I think I know – something Biden seems to understand – is that an indefinite military occupation of the country is unlikely to fix this in a practically sustainable way. There just have to be other institutions more suited to bring about this kind of transformational change with staying power. It is magical thinking, for instance, to conclude military force can keep prideful, exceptional STEM girls excelling for generations to come

And while STEM is great, imagine the simple gift of learning to ride a bike

How did you come to this worldview regarding Afghanistan?

Twenty years of paying close attention and a slow read of the book Directorate S by Steve Coll. Steve Coll won a Pulitzer prize for Ghost Wars, which I understand is an equally eye-popping book.

I want to turn to domestic matters now. Your wife – Happy Wife we understand you call her – we’ve learned has recently resigned her position at the medical practice where she’s worked for the past twelve years. How are you two doing?

We are well, thank you. She resigned sooner than she’d planned to, a year ago we thought it’d be next year. But circumstances at the practice changed, or, I should say, didn’t change, so it was clear to her now was the time to go. We’re debt free, we’ve invested well. I’m pleased as punch to begin the next phase of our lives with this woman, truly I am

How about you, care to describe the arc of your professional life?

I’d call it more a sinusoid than an arc. I’ve always been intellectually restless, never able to settle down long enough to become a rock star in any one field of work, and then climb an organizational ladder to manage people as though I was. I’ve enjoyed a couple leadership roles over thirty-five years, but by and large I’ve been a rank and file worker, whether in the commercial or academic space. I like to learn new things. In some cases completely new things. I like to say that when I matriculated the biomedical science program in Pharmacology at Case Western, I didn’t know a mitochondria from a nucleus. I had some chemistry chops, but the mol-bio part I had to learn pretty much from scratch. Case was a fantastic place to do that.

Not counting grade school, I’ve spent about eighteen years of my life in school, part- or full-time. So by now, at LinkedIn, my headline skill set reads: Researcher | Software Developer | Geophysicist | Husband . Not necessarily in that order 😉 Overall, it feels like a win, but in terms of fulfillment, yeah, it’s been a roller-coaster.

Will you two stay in Alaska?

Certainly for the near term. We have plans to travel Outside next year more often and for longer than we have in past years. Even Black Dog will join us on certain adventures! He’s pretty jazzed about that. We’ve talked about moving, likely somewhere in the northwest if we do (Happy Wife cannot do southwest), but the combination of high home prices right now and being we’re pretty picky about the community we see ourselves settling into, it’ll take time. So for now we enjoy the summer lilies and the flourish of Amanita popping up among dwarf dogwood. A walk in the woods with Happy Wife and Black Dog is a good day

… working on the next post. 😏

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.