Ramblings: July/August 2023

24 September 2023

Below are collected Twitter ramblings for July and August 2023, with the usual additional commentary interspersed. I combined these two summer months due to taking some long stretches of vacation where I wasn’t posting very much.

This month’s photo of the month was taken on a small peak unofficially dubbed “Wizard Mountain” near the Head of Dean camp at Philmont Scout Ranch in Cimarron, New Mexico. Sunsets in the Sangre de Cristo mountains are uniformly spectacular.

I’ve received some feedback that some of my comments are a little too skewed toward pitting academia against industry, and/or give the impression that it’s all sunshine and roses in industry. So let’s be clear: while academia certainly has its share of issues to sort through, so does industry. We have portfolio reprioritizations that will kill your project, reorganizations led by MBA-types that will cut your job — not realizing that reducing research activity to save money / boost margins now is cutting off your nose to spite your face, soul-crushing bureaucracy (particularly in big pharma), and more. There’s also a deep moral objection that some folks have to pharma being a for-profit business at all, which can lead to a mindset where academia is placed on a pedestal. So there are no perfect jobs, just different trade-offs. Read the comments on Jeff’s post to see some of the craziness.

It’s the Next Thing, and it’s got a less awful UI than Mastodon. But I’m not sure it has the user base to stick. Right now it’s also invitation-only, which I think is giving the “Twitter is toxic” crowd a false sense of security. There’s no reason to believe that when Bluesky goes wide, it will not achieve comparable levels of toxicity. My levels of engagement remain far, far higher on Twitter, or X, or whatever we’re supposed to be calling it these days. But I’ve established a presence on Bluesky anyway — just in case the audience shows up one day.

Best two weeks unplugged ever. We had so much fun on this trip, even though it was challenging!

Everyone’s PhD experience is likely to be different. We all bring in different levels of knowledge, experience, and physical and emotional preparation to do the thing that’s probably the hardest thing (or among the hardest) you’ve done in your life to that point. I brought a decent knowledge base, but not a ton of lab-based research. I brought the confidence of youth, but also the doubts and feelings of inadequacy of being a first-gen grad student. I brought my suburban life experience to the biggest city in America. Grad school will challenge you, shape you, change you — and I was fortunate that it turned out mostly okay for me. There were so many points along the way where it could have gone sideways though. So I think we should all try to have a little more understanding of those who have struggled, or are currently struggling. Providing support is more work than being dismissive, but also the right thing to do.

I’m often struck how many other lines of work besides pharma one can go into where hard work can be easily and directly equated with success. Here’s a business where you can bust your ass, do everything right, and still fail the overwhelming majority of the time. Statistically, the average drug discovery scientist will go their entire career and never work on a project that leads to a marketed drug. Getting even one is beating the odds. If you want to just work hard and be successful, there are many other lucrative lines of work one can go into besides drug discovery.

Ah, the beginning of the room temperature superconductor saga.

I wanted so, so badly for this to be real, even though I also knew the odds of these findings panning out were low. This is one of those things that would be a huge technological revolution; it’s the foundational stuff of science fiction. There have been glimmers of hope before, and all have been crushed by the onslaught of confirmatory experiments. I still hope I live to see it happen for real someday.

In due deference to Dr. Meldal, who I don’t know and whose Nobel was well-deserved, I don’t place blame with him. We all see this kind of thing happen where a photographer wants to stage a photo, e.g., for the Nobel Prize social media feeds, and they push scientists into situations where they do things in a lab setting that look cool but are decidedly below normal safety standards. Probably the most egregious example of this kind of thing I know of is a famous photo of RB Woodward smoking in lab around the time of the quinine formal total synthesis. Although in Woodward’s case, it’s questionable whether or not this was normal behavior for him since he was a chain smoker. Anyway, I wish there was a way to exert more influence when scientists intersect with journalism. Nobel laureates are role models that other scientists will seek to emulate.

If you’ve never tried the Oppenheimer martini, you can find a recipe here. Basically it’s a giant dollop of gin, a hint of vermouth, and a lime-honey rim. A bit like a deconstructed Bee’s Knees, for the cocktail aficionados out there. Oppie’s originals featured a whopping 4 ounces of gin, so usually one will do you nicely. Two and you will need a designated driver.

We often forget the origin of the phrase “critical mass” in nuclear physics, but its generalized meaning of sufficient density for a self-sustaining reaction has found broad applicability in business and elsewhere. Unfortunately, it’s also misapplied as an excuse, as in the case above. Large organizations don’t always grasp that sometimes a small, dedicated group can achieve some pretty amazing things. Especially when you let them do their thing and clear all the red tape from their path.

This behavior, more than anything else, will drive people out of science. It only takes a moment to be kind, to thank someone, to tell them they did a good job — but it will immeasurably brighten that person’s day, especially on a day when they might be struggling. There’s even research that suggests high performing teams have a praise-to-criticism ratio of >5 (!).

Scientists are goal- and detail-oriented and driven. You have to be in order to cope with all of the daily failure, of which there is a lot. But this also generates a tendency to look for flaws and mistakes, which are then microscopically examined and picked over. This is a great technique to apply to troubleshooting your failed reaction, but a shitty one to apply to people. Every scientist is also a human being and wants the same emotional comforts that most humans want.

So much of the workplace frustration that I hear on Twitter — academia or industry or otherwise — stems from a basic lack of compassion for other people. The good news is this is fixable. The bad news is, if you lack people skills and nobody tells you that you can learn them and improve — just like any other skill — the toxic culture is born and propagates.

You don’t get what you don’t ask for, so ask. Part of negotiation is finding out where the limits are, and they’re often further than someone making you a job offer will want to say. Because they’re negotiating, even if you’re not. A good organization that wants you as part of the team will not be offended or rescind an offer because you negotiate. But they’ll also happily onboard you for as little as you’re willing to accept.

I hate this practice so much. It’s a relic of a bygone era that might be making some copy editor’s life easier somewhere, but it’s useless to a reader. Especially in a time when folks are increasingly reading their journals electronically. I’ve been reading on my tablet for many years now, and I’m never going back to paper. Just put the damn figures in the text near where they’re mentioned in the text.

This surprised me. I ran across it while generating IUPAC names for a patent application and thought that surely there was some error in the name generation — but no. I get the logic, but I’m probably too old to adapt and will cling to cis and trans until I’m dead.

Twitter (or X, or whatever) provides a good deal of levers for you to pull to control what you see in your feed, but I sense most folks don’t even know that they’re there. There’s plenty of ways to train the algorithm to suit your needs besides mutes and blocks, which are the bluntest of all instruments. Give some of them a try and see if it helps. Above is just one tip. There are others.

I learned this after not checking my email while I was on sabbatical for 6 weeks last year. I had like 1500 messages waiting when I got back; less than 10 of them required any significant action on my part. “This is important, I need to respond now.” “This isn’t that important, but I can answer this one quickly, so I’ll respond now.” All falsehoods. So many of us chain our workday life to email. Break the chains.

Simply put, fraction absorbed is bioavailability that’s been normalized for clearance. You can’t truly understand absorption without a correction for the first-pass effect.

I have no idea where this meme of Einstein, Ken, and Oppenheimer came from originally, but I was all too happy to roll with it.

Hit validation is its own art form, but part of it should include an independent resynthesis, preferably via an orthogonal synthetic route. For those who are not medicinal chemists, consider the relatively recent case of a claimed Pd-free Suzuki coupling. The eventual debunking of this work was achieved, in part, by synthesizing the ligand via a different route that didn’t involve the use of Pd chemistry, and thereby avoided the Pd contamination in the original route that was likely driving the coupling. Same logic for screening hits.

Fort Meade — home of the National Security Agency (NSA) — is relatively close to where I grew up, and I’d heard over the years that the cryptologic museum is top-notch. It had been closed for a while for a major renovation, but we finally made the trek on a trip home over the summer — and it did not disappoint. They had all kinds of goodies, including working Enigma machines. My kids delighted in sending each other coded messages. This exhibit on Oppenheimer was, by the museum’s own admission, a little opportunistic in coinciding with the movie release over the summer — but I enjoyed it anyway.

I’ve deliberately not taken a side in the whole “Elon owns Twitter/X” debate, because the platform is my preferred social media, and I don’t have a lot of time to invest in alternatives. I also don’t see that view changing much as a consequence of who the owner is, and I actively curate my feed so that it isn’t overrun with garbage. But… statements like this are just needless. Part of curation should be that people have the ability tune out other folks, especially if they’re being actively harassed by anonymous strangers. (I also think that, with limited exceptions, people should have to make their identities clear and not hide behind anonymous troll masks, but that’s another post.)

Pharmacological utopia: within reach.

It’s astonishing to me how often people will spend the money to run PK studies and then not get this order-of-magnitude-cheaper-but-still-critical piece of data to go with it. There can be no meaningful attempt to interpret a compound’s in vivo pharmacology without understanding free drug levels. Some form of plasma protein binding data is the bare minimum to do that.

This has been a huge organizing principle for my life. It’s so important to have awareness of how you’re spending your time, and to make active choices. I have news for you: nobody is “doing it all” — even those who seem like they are. Some folks are, however, better at time management. And I don’t mean scheduling your life in 15 minute blocks, sleeping 4 hours a night, or whatever. I just mean actively thinking about what you’re spending time on, and confirming with yourself that this is what you want to spend it on. For example, I made a conscious choice that I’d write a Substack post once or twice a month. It takes me an hour or two to write this up on a Saturday evening or Sunday morning. I’m okay dedicating time to it because I like to write and this is an outlet to scratch that itch that’s not too time-consuming.

I see lots of posts on Twitter about folks not being able to imagine how other people do “X” — whether X is changing jobs, settling down with a partner, buying a house, having kids, or any other major life change — when they can barely stay afloat now without doing any of those things. When I was 25, I had done none of those things either, and had the same doubts. By 35, I had done all of them.

The solution isn’t magically creating more hours in the day or micromanaging your day down to the minute — that latter one usually backfires spectacularly unless you can muster a herculean discipline that almost nobody has. Instead, the solution comes in making conscious choices about what you want to spend time on. I bought a house — so that means I will now spend some hours mowing the lawn, doing minor interior repairs, etc. I had kids — so that means I’ll be spending a big chunk of time with them, especially when they’re little and fully dependent on you. Along the way I gave up: routinely spending extra hours at work, a lot of pleasure reading time, going to every first-run movie every week with my wife (now we’re mostly Netflix and chill), going out to restaurants every week (too expensive anyway), watching TV (I watch almost none these days), playing video games (ditto), and more.

I regret none of these decisions, because my life is full of other things that I now value more in comparison to what I previously spent time on. The new thing isn’t something to cram into your already-full life; it will displace something else. Everyone will reach their own conclusions and find their own life equilibrium. I’m not advocating that you jump up and do all the big life things, because everyone’s circumstances are different and there is a level of privilege baked into my own story. If I have advice, it’s simply to occasionally actively think and make choices about how you spend time, instead of just spending it. The meter keeps running whether you think about it or not.

I was astonished to hear this story about how blue crabs are considered an invasive species in Italy. Meanwhile a dozen steamed blue crabs in Maryland can easily run you $100. My offer to help Italy with this problem stands.

These two go together. Med chem and process chem have a long history of having a little fun jabbing each other. We both know exactly where the other is coming from and why we do things the way we do. But sometimes we like to pretend that we don’t.

My freshman year math teacher in high school helped score me the only “D” grade (nearly-but-not-quite failing for non-US readers) that ever appeared on my transcript. The dude was just a lousy teacher who couldn’t connect with students and didn’t put the time in to help people who were struggling. I spent most of high school convinced that I was “math dumb”. I muddled through the courses, but ultimately did make it to Calculus AB — the lower section of advanced placement calculus. The only reason I landed in that class is that I took probability & statistics the year before and had a fantastic teacher who also happened to teach AB calc. I followed the teacher, and he got me back on track to loving math. Never underestimate the power of a good teacher.

Regular readers know that AI-based drug discovery shows up on the regular in my feed as something of a punching bag, but I’ve also always been clear where the line is. I think AI has the potential — heavy emphasis here on potential — to be a transformative approach to drug discovery. It’s a hard business, and more tools in the toolbox are sorely needed. In that respect, and especially in the arena of ligand discovery, I welcome what AI/ML tools can bring to the table. What I strenuously object to, though, is the rampant overselling of what AI can deliver for drug discovery today. There are no panaceas in drug discovery. A little humility goes a long way to establishing credibility.