Ramblings: April 2024
19 May 2024
Below are collected Twitter ramblings for April 2024, with additional commentary interspersed.
This month’s photo of the month is (I think, as my bird ID skills are poor) a great egret I spotted noodling around our resort while visiting the House of Mouse in Orlando, Florida.
If you’ve been following me for more than five seconds, hopefully you got the joke. As has become tradition, note the date on this post.
The beginning of April is the height of conferencing activity for me for the year. This year, I attended (and presented) at both the CHI Drug Discovery Chemistry (DDC) and American Association for Cancer Research (AACR) meetings. As fate would have it, both of these meetings were in San Diego, back-to-back — and San Diego is, without question, my favorite conference venue in the USA. Great food, excellent weather, easy access to convention facilities, amazing scenery along the coast, and — rocket launches?
I confess to being a space junkie. I grew up in the Space Shuttle era, and was that nerdy kid who had his parents record shuttle launches (on VHS!) if I happened to be in school during a launch. Although in those days, it was common for a teacher to wheel a TV into the classroom so we could watch live, as that was deemed suitable enrichment. Of course I remember when we lost the Challenger, as clearly as if it was yesterday, even though I was only 9. And later when we lost Columbia. But then, from around 2010, something far greater: we lost our way.
We stopped flying the shuttle, and seemed to have lost our aspiration to go anywhere beyond low Earth orbit and the ISS. We started on Constellation, then stopped, then it became SLS, spent a mint on it all, and have had one launch since. We were going to Mars, or back to the moon, or wherever the current administration deemed electable when they stuck their fingers in the wind. An entire generation came of age with no cohesive space policy, and I think stopped caring about space as a consequence.
The commercial crew program, although controversial when it started, has kinda worked out. We’re sending humans to space again on our own rockets and spacecraft. SpaceX is undeniably leading the charge on this front, and they’re also daring to dream that big dream again: to go back to the moon, and on to Mars. Say nothing of the amount of planetary science we’re going to be able to do when we can yeet 100+ metric tons into deep space for 100x less than it costs today — are we doing anything to get ready for that future?
I realize many folks have their issues with the owner of SpaceX — I do too. But that’s also a big organization full of super-talented engineers who shouldn’t be judged by the words and actions of one man, and they’re doing some pretty amazing stuff once you look past the Elon hate. They’ve made spaceflight so relatively routine now that this big kid can see a rocket launch from his Uber while driving to a hotel, and take a picture of it, and that’s just a normal thing in 2024.
Okay, back to med chem now — promise.
One of the true delights of going to conferences is finally getting to meet some people in person that you’ve only known through the interwebz. Really enjoyed getting to hang out with Andy at DDC, along with a number of other folks I met for the first time.
If you’ve never heard Barry Sharpless lecture before, trust me that the fact he asked for a flip chart to riff on at the end of his regular lecture is entirely on-brand. Honestly, even the regular part of the lecture with slides was more of a loose guideline than something strictly followed. Listening to a Sharpless lecture means buckling up and accepting that you’re going to get in the car and go careening off in whatever direction his mind feels like going in that moment. If you try to fight the current, you’ll walk away bewildered. But if you go with the flow, you get a remarkable insight into the nonlinear thinking of a genius. And he has two Nobel Prizes to prove it.
I confess that the tweetorial I promised on volume of distribution has now been repeatedly delayed by outside circumstances, and I’m not very close to delivering a final product. But I will underscore again here that volume of distribution usually says nothing about the extent of drug distribution in a way that impacts pharmacology. Pharmacology, of course, is affected by free drug, not all the drug non-specifically bound to plasma or tissue proteins. The free drug hypothesis tells us the true extent of free drug distribution throughout all compartments of the body: at steady state, it’s the same everywhere.
Where people get misled, as they do by many PK parameters, is by forgetting that volume of distribution is a total drug, rather than a free drug, parameter. It’s true that the concentration of total drug can be very different between plasma and tissues. If it’s much higher in tissue than plasma, volume of distribution will be correspondingly higher. A simple case where this is often seen is with compounds containing basic amines. Such amines are generally positively charged at physiological pH, and like moths to the flame, they are inexorably drawn to the negatively charged phospholipids that make up cell and other membranes. But the key point is that it’s precisely these non-specific binding interactions that are driving the tissue distribution! Setting aside all of the non-specifically bound drug, we should still find in most cases that free drug is the same everywhere. So we should stop promulgating the myth that drugs with low volume of distribution don’t effectively penetrate tissues to reach the site of action. This is nonsense on the level of free drug.
Having been part of a generation that grew up with computers, it never ceases to amaze me how inept many scientists are when it comes to making a PowerPoint presentation and getting it to run on someone else’s computer. This is a foundational communication skill that any practicing scientist today should possess, and it’s worth the effort to polish your presentations and overcome vestigial technophobia.
This joke was deeply under-appreciated when I made it, so here I provide a link to Robert Frost’s classic poem “Fire and Ice” for those who slept through freshman English in high school. It was also used as an epigraph for the latest Ghostbusters movie, so no excuses really.
Most years at the AACR meeting, I’m happy to just represent the Chemistry in Cancer Research working group. They have an active chemistry community and it’s been fun to participate in and promote their sessions at the meeting. But this year:
Will you speak at an educational session? → ribbon
Will you review abstracts? → ribbon
And btw will you co-moderate a TPD abstract session? → ribbon
For those who are not privy to a long-running inside joke, there is a semi-seriously held belief in some corners of the Twitterverse that Ingo and I are the same person. We share a lot of the same opinions about medicinal chemistry, pharmacology, and drug discovery, and nobody had ever captured us in the same photo in the wild. (Ingo is actually somewhat camera-averse as it turns out.) Anyway, the myth has been busted thanks to some good-natured cajoling from Danette Daniels.
What other slang is slung in your shop, folks? I experienced this in the early days at my current employer. Biotechs startups are often a big melting pot of people coming from other corporate cultures, and sometimes they bring words and acronyms with them without realizing that they’re not quite as universal as they seem to believe. We had a number of ex-BMS colleagues who would go on about getting a CRC. What they meant was “concentration-response curve” — but meantime I was like, “Why are you talking about colorectal cancer?” In many circles we’d call that a dose-response curve (or DRC), so just be careful before you start dropping acronyms!
I’d caution against getting old, but the truth is: in most cases, it beats the alternative. Take care of yourselves and manage the decline though. What’s easy at 25 gets a little tougher at 35, and tougher still at 45. Exercise is one of the few remedies we have, so don’t neglect to take care of the only body you have!
A certain CFO I know can tell you a story about a chemist who, many years ago now, came into a startup armed with comps and a distrust of the future value of pre-IPO shares, and fought like hell for a salary increase over the offer letter. The chemist won that round because they had done their homework and held out.
Another piece I’ve been noodling on is my own story of when the real-world impact of drug discovery finally sank into my bones and I really felt it. Unfortunately, it’s another piece delayed by some outside factors. But I do have a rough draft of this one at least, so — maybe by the summer?
Somewhere around the 10-15 year mark into your career, at least in pharma/biotech, you’ve been around long enough to develop a decent mastery of the scientific principles needed to be successful. And hopefully that means you’ve had a few rounds of reducing those principles to practice, which is where most the learning happens. After that, well… it’s not that you stop learning, because learning is (or should be!) a lifelong thing. But you do reach a level of diminishing returns on science.
If you’ve got your eyes on those higher rungs of the career ladder, people skills become paramount. It’s no longer enough to have a strongly held scientific hypothesis and charge up the hill on your horse. No, now you have to wave a flag while on your horse and convince other people to charge up the hill with you — even if the odds are stacked against you. And in drug discovery, the odds are always stacked against you. Drug discovery is not an occupation you can do alone — it requires a lot of people with diverse backgrounds. The leaders who can marshal the team to do the work and to believe in the work are the ones who will rise to lead the organization. Develop your skills accordingly.
I find that almost every instance of looking at data and feeling uncomfortable means that something is missing. Usually it’s a pivotal experiment that will distinguish A from B that’s being avoided for any number of reasons: it’s too costly, too difficult to execute, will take too long, we lack the expertise to know what the right experiment should be, or more often, we’re afraid of what the outcome will be. Or any or all of these things.
Smart teams and team leads don’t ignore the discomfort, but confront it head-on and push for the right data to be gathered despite the obstacles. Failure to do so can lead to projects that become zombies: they keep going and going. Always sniffing around the periphery of success (or at least, making a decision) — but never quite getting there because they keep doing the wrong experiments and hoping the one they know they should do will go away. Hope is not a strategy.
It was a bumper crop of real life meet-ups with Twitter friends this month. I had awesome day hiking with KC and then getting some beers. (Congrats again on the new job too!)
Our friends at Encyclopedia Britannica have a nice summary of working with significant figures, so here it is. The most common error I see people make is things like the above where IC50s are reported to three decimal places, because this is what fell out of some curve fitting software. But the software isn’t going to respect sig figs, because it doesn’t know the precision of your measurements. You have to do that work yourself, and frankly it’s not a great look when you neglect to do something that most of us learned in high school. The guiding principle to remember here is that a calculation can have no more significant figures than the least precise measurement that went into it. So unless you’ve gained the ability with your liquid handler to know your dosed drug concentrations accurately (on nanomolar scale) to three decimal places, you better dial back that IC50 precision.
It’s a very strange defense to me that because something was peer-reviewed and published, it’s then beyond reproach. The amount of fraud and fakery in scientific journals has proliferated — a combination of seedy publishers who are happy to look the other way for a fee and enough researchers (if you can call them that) who are willing to use ever-more-sophisticated means to try and game the system for prestige and grants. The biggest loser in this race to the bottom, of course, is all the rest of us. How do we distinguish truth — the central tenet of science — when so many are polluting the process with fiction for their own ends?