Ramblings: November 2022
30 December 2022
It’s the start of the new year, and look at that: I’m almost caught up on my monthly Twitter ramble Substack posts — yay! Here comes the November edition, with usual commentary sprinkled in.
This month’s photo of the month was taken along the eastern ridge of Ragged Mountain in Berlin, CT. This is a challenging hike to a flat-topped summit along the Metacomet Ridge. It’s one of my favorite hikes in the state.
What other reagents out there need a clever acronym? Tell me your favorites!
I editorialize extensively when I’m reading; I can’t help it. It rarely makes it into anything I might write in public though. It’s more for organizing my own thoughts. And in fairness, there are also plenty of times when a big ol’ “!!!” will appear in the margin when I find something particularly cool or exciting.
Still waiting to see if anything comes of those lawsuits from all the laid off Twitter employees. My guess is no. Current management may be crazy, but they also have scads of employment attorneys paid to keep things above board.
This was the beginning of what became a fun series of polls! I even learned a few acronyms I hadn’t heard of before along the way.
In the style of March Madness.
Nothing beats a good acronym. And who doesn’t like Admiral Ackbar?
Shortly after the change in ownership of Twitter, the great Mastodon & Post migration began. I was not a fan at the outset, and I’m still not really. The audience is small but the echo chamber is big. I feel like there’s a lot more opportunity to reach folks and build an audience on Twitter. Since I’m a user of “latest tweets” rather than the algorithmically-driven “top tweets”, a lot of the garbage that people are upset about seems to have never made its way onto my screen. There’s a surprisingly good deal of control and curation you can exercise over your Twitter feed, but I sense that a lot of people just go with the defaults and haven’t tried to take greater control. It doesn’t help though that Twitter has done a terrible job of advertising and educating on their customization controls. It helps even less that their default algorithm is dogshit. But I don’t think that’s anything new under the new ownership: the algorithm has always been dogshit.
I’m writing this post in the depths of winter, and taking slim comfort in the fact that there’s exactly one more minute of daylight today than yesterday.
This theme of life science PhD labor market economics just won’t stop coming up. There are some serious structural issues to address here. The main thing is making sure folks are aware of all of their employment options while they’re still pursuing their PhD, and not locking in on academia as the only/preferred option. I’d much rather view the employment tent as a big one, where we’ll hopefully find gainful employment for most in one sector or another. Chemists have been unusually fortunate over the years to have chronically low unemployment rates.
It comes as little surprise to me that an OG acronym like DEAD would carry the day. It has just the right combination of nostalgia, synthetic utility, and cleverness.
Hustle culture only seems like a good idea until you get too old to hustle. You’ll wake up one day and realize that some of the best years of your life were filled with work and little else. My biggest regret from when I was an undergraduate student? That I didn’t have a little more fun while it was still easy to do without obligations.
We as a discipline can do more to build a holistic approach to employment. Let’s go out of our way to show people all of the options early and regularly during their educational journey, and trust that they’re smart enough to forge their own paths. Cultivating the notion that academia is the peak career is… a little cultish. I sense there are some PIs out there who believe they increase their own glory by having a network of glittering academic PI jewels who came out of their labs. But that’s more about the PI than the student, isn’t it? Shouldn’t the right course of action be to celebrate the career successes of all students, regardless of which path they eventually take?
Offer still stands. I love doing university visits, and would love to visit yours and meet your students, even if virtually!
Maybe it was just a slow news month, but it felt like it was time to set down a handful of truths that I’ve come to appreciate about drug discovery over the years. This one is about not getting too caught up in the hype. Executives tend to love the hype because they’re looking for something to fix all the problems this business has. It’s an illusion. Use the tools available, but be aware that they’re just that and nothing more: tools.
The person who’s telling you they’ve found some amazeballs way to shave a year off any part of the drug discovery operation is either delusional or, more likely, riding a giant Dunning-Kruger high because they haven’t been doing it for long enough to know better. What goes around, comes around. This is why I currently have such an aversion to the Silicon Valley invasion of drug discovery. That crowd is used to every problem being reduced to an engineering problem that can be coded into submission, and human biology isn’t that neat and tidy.
If a piece of data, or lack thereof, is nagging at you, don’t ignore those feelings. Press on them with experiments and data. This is the way.
I have no idea who’s running social for Sigma-Aldrich these days, but I like them.
A year in the making, this was fun to write with my colleague Erika Araujo. Sadly it’s probably already time for a sequel book. TPD is moving so fast these days that the chapter we submitted in the late fall of 2021 is getting a bit dated. Clinical trials in particular have really taken off across the sector in the last year or so.
This, I think, is the real art of drug discovery: honing your senses to know when it’s right to take calculated risks and say yes. We’re still wrong a lot, of course. But I can’t help but wonder how many might-have-been drugs went to their graves for bullshit organizational and administrative reasons.
Another perennial holiday dinner conversation with opinionated relatives. Between Elizabeth Holmes and Pharma Bro, sometimes it’s a race to the bottom. Laypeople don’t know the difference between these hucksters and the rest of us, and they don’t care either. No matter how much we try to distance ourselves from these kinds of shenanigans, to the general public, we’re largely no better than our worst constituent part. No idea what to do about that either, except for us to be better and call out bad behavior when we see it.
This one is really about proper time management. Drug discovery cycle times are already long, and we can do our part to not make them longer by planning appropriately for syntheses. There are forever hidden needs for additional milligrams (or grams later in the process!) — so many that it’s easier to just pad the synthesis than to try and rationally predict them all.
Time management again. A simplistic way to frame this calculation: pretend you have a blockbuster drug on your hands with a potential $1 billion in annual sales. Since patent lives are finite and you’ll face competition from generics sooner or later (ever sooner these days), every day of waiting once the patent clock starts running costs you $2.7 million a day in sales. Even if you factor in there’s only a 1 in 20 chance that your drug/project will make it (about right given current clinical failure rates), that’s still $135K a day. The tens of thousands of dollars we’re talking about to run studies in discovery is usually well into “small potatoes” territory in comparison. Skimping on stuff in discovery winds up getting done for budgetary reasons, but it’s often penny-wise and pound-foolish.
Beyond my love for True Grit, whether it’s Charles Portis’ novel or either of the movie versions (the Coen Brothers adaptation is far better and more faithful to the book), Rooster Cogburn is our spokesman. If you can’t play a long game, drug discovery is not your game. Or at least not one you’re likely to find much happiness or fulfillment from playing.
Especially true in medicinal chemistry, where so few of us have a hardcore background in medicinal chemistry from our graduate school days. Historically, most medicinal chemists have trained as synthetic organic chemists. Industrial pharma outfits know what they’re getting with new hires: folks who know how to make molecules who are going to have to be trained on just about everything else related to the craft. Sometimes the new hires themselves don’t realize this, however. I’ll also note that I’ve seen some turning of this tide in the last few years, with more people being hired out of academic med chem programs. Even there though, the practice of medicinal chemistry is often very different in industry than it is in academia. For one, they have different goals. Industry is exclusively focused on discovering drugs. Academics may be doing that as part of their program, but it’s rarely all of it. Going along with that difference, there are vastly different scopes in the number of assays (particularly in vivo) and, frankly, dollars that industry has access to.
Thanksgiving is my favorite holiday. An old saying goes that you shouldn’t trust a chemist who can’t cook, so I take my measure of pride in the many years that my wife and I have hosted Thanksgiving at our home. Everything begins with good turkey stock, which I always make from scratch the day before. Stocks and soups almost universally need “melding” time and improve with a little aging. An overnight stay in the refrigerator makes a big difference.
Already wrote about this elsewhere, but I think a big chunk of being satisfied with Twitter is how much control you take over your own feed. Ditching Twitter’s algorithm was my #1 quality of life improver.
If you’re not this dedicated to your turkey, are you really serious about Thanksgiving?
When I started my Twitter account 6 years ago and began posting about drug discovery and my little corner of the medicinal chemistry universe, I never imagined it’d attract much of a following. And maybe by Twitter standards, 5000 followers isn’t huge. But it’s about 4900 more than I thought would care about what I had to say. So thanks for coming along!
More hiking photos - from the same place that the “photo of the month” at the top was taken.
This is really two issues rolled into one. First, the absurd number of significant figures. If someone tells you they’ve calculated an IC50 accurately and precisely to three decimal places, they’re either: a) delusional; b) lying about it; or c) spent their entire PhD program generating replicates to statistically power such an observation. Of course, the standard deviation tells you what the right number of significant figures is, and it’s a hell of a lot less than three decimal places! But the second, bigger issue is the use of arithmetic statistics on geometric data. Anytime you see a mean +/- standard deviation on dose response data, it’s wrong, full stop. Geometric means times/divided by a geometric standard deviation is the only appropriate way, unless the data has been log-transformed. Normal error in a well-behaved biological assay is 3-fold, or half a log. Anyone who isn’t telling you that? Yeah, they don’t know what they’re talking about.
It may be my imagination, or my increasing age, but I feel like the number of grammatical and spelling errors that have crept into journals has gone up dramatically in the last 5-10 years. No hard data to back that up other than my own irritation though. But sometimes you run into one like this one and you can’t help but chuckle.