Ramblings: March 2024

28 April 2024

Below are collected Twitter ramblings for March 2024. Color commentary throughout.

This month’s photo of the month is from an overlook on the Ives Trail in Danbury, Connecticut. Unfortunately there are still a lot of gray days in Connecticut at this time of year, but the flip side is the trails were quiet.

When I talk about how industry and academia have different value systems, this is at the core of what I mean. Academia values the creation of knowledge and, necessarily, its broad dissemination via publication to the community of scholars. Industry values the application of knowledge to a practical end and, necessarily, often needs to keep those applications patented and shrouded from the view of competitors.

Now, these are not black-and-white distinctions. Practical applications do come directly out of academia, and there’s way more basic research going on in industry than people realize. I can think of several examples over the years where academic groups published papers and made a splash on things that my colleagues and I had worked out years before — but couldn’t publish on. When industrial folks do publish, it’s usually a safe bet that whatever they’re showing was figured out 5+ years ago. Our knowledge today is at least that far ahead of what we’re publishing on. To work in industry, you have to center that publishing your results as fast as possible is not the goal.

None of this is to pass judgment on either value system either. Both are useful in their own ways to society, and neither is perfect. Given the high entry and development costs and the enormous risk of failure, pharma companies need the profit motive to drive innovation. The cost is not sharing what we’ve learned as soon as we can after we learn it, which rankles the academic value system most of us experienced before industry. But this doesn’t mean that the industrial value system is wrong — it’s just different.

Late March and early April tends to be peak conference season for me. As a drug discovery scientist working in oncology, the American Association for Cancer Research (AACR) annual meeting is at the top of the list of “must-go” conferences, and most years it falls around this time. They have a robust Chemistry in Cancer Research (CICR) working group, and the New Drugs on the Horizon first-time candidate disclosure sessions are among the most popular at the meeting. As fate would have it, I was also invited to speak at CHI’s Drug Discovery Chemistry conference this year. Both DDC and AACR were held in San Diego, back-to-back. I’m never going to cry about going to San Diego in April, when the weather in New England is still raw.

Well this blew up. I knew the chemistry community would come through with their stories of broken glass, but there were so many! This post caught enough attention that it got write-ups in both Chemistry World and C&EN too. Solidarity abounds in the chemistry community, despite an ever-more-divided world around us.

Down the east coast in the Research Triangle of North Carolina, you’ll find Oerth Bio, a joint venture between Arvinas and Bayer Crop Science, working on degraders for agricultural applications. Many years ago, RTP was my old stomping grounds from when I started my career at GSK. The majority of the senior folks in chemistry at Oerth are ex-GSK, and I know all of them. It was delightful to reconnect with these guys when they came up to New Haven for a consulting visit. I haven’t seen any of them in person since I left GSK 16 years ago!

Who knew four words would gain this much traction? Sometimes simple truths resonate.

Most scientists I know working in drug discovery have some fire in their bellies. It can come from many sources, but most often comes from the loss of a loved one to a disease catalyzing a desire to use their talents to do something about it. If that comes off as us seeming a little angry, well, maybe we are a little angry. People don’t always share that they have something burning inside them that drives them, or why — but that doesn’t mean it isn’t there. And I think that’s all okay.

When you land on a hit tweet with “drug discovery is hard”, the next logical step is to frame it like Douglas Adams would so that everyone outside the industry gets it.

Short version: inside the industry, we use “drug” as a pharmacology shorthand for any compound tested in just about any assay. Outside the industry, I recommend that we use “drug” to refer only to approved and marketed drugs registered in a pharmacopeia or formulary — or at least append “investigational” in front of things in trials. The public imagination already has a poor understanding of what drug discovery scientists do, and it doesn’t need to be further clouded by careless use of terms.

Some of the replies here surprised me, and it seems that at least some folks out there are doing these consulting sessions for extra cash. For me anyway, I just don’t have a great feeling about it. It’s a fine line to ride between providing background information and educating a competitor on things they need to learn on their own — and I’d rather not ride the line at all. In any event, I feel like I’m fairly compensated for what I do and don’t feel the need to give up more hours of my non-work time to do more work for hire.

I wrote about this at length before, but this 3x rule applies to most assay data. Data from biological systems follows a log-normal distribution, and it’s extremely common for error to be half a log, which is ~3x. An IC50 of 10 nM vs. 30 nM for two compounds is generally not different enough to make SAR decisions on, unless you have a large enough number of independent measurements to narrow the error down. This latter condition is rarely met though, as most compounds are going to get an n=2 in routine screening mode. And don’t @ me about the error being +/- a standard deviation. If you’re reporting error this way, you’re doing it wrong, full stop. Log-normal data should use geometric means and standard deviations.

If you’re unhappy in your current job, this is for you. Especially if you’re early in your career, there’s ample time to take some risks and recover if things don’t work out down the line. Being willing to make a leap — and realizing that you’re empowered to take charge of your own career — is the key to not getting trapped in a corporate drone job for life that you hate.

Part of the job when you move up the chain a little bit is making decisions about where to spend your time. It’s rare that a week goes by where I don’t have overlapping meetings from two or more teams who invited me to participate. I’ll often ask teams what they plan to cover and/or need my input on, and make decisions accordingly. I’ll always favor a team that is at a crossroads and needs strategic input over one that’s just doing an informational update.

Not far from the truth, because I doubt either Jensen or I will see this dream realized in our lifetimes — if it can be realized at all, which I also doubt.

I’m not a fan of extensive editorializing in journal manuscripts. A little speculation about the future and new directions to take the work is fine. But using superlatives like those above to describe your own work is just above and beyond.

It’s the same reason I’m on a mission to reduce the use of adverbs in scientific writing — because they’re often unnecessary editorializing. Consider my favorite scourge: importantly. Importantly according to whom? The authors, of course. It’s an opinion. And furthermore insults the intelligence of the reader that they couldn’t judge for themselves what’s important in a manuscript without the authors spelling it out for them. If it’s so unclear that you need to spell it out, maybe consider tightening up your writing?

None of this is to say that we don’t have and value relationships with scientific vendors — of course we do. But I also have a good understanding of what my needs and the needs of the folks in our department are. The chances that there’s some amazing opportunity out there that’s going to revolutionize my work life — if only I knew about it through a cold call email — are low.

Therefore I can’t spend lots of time on such things, particularly at conferences. Conferences are infrequent events for most industry folks, and the time there is precious. Learning about the latest breakthroughs — and keeping tabs on what our competitors are up to — has to be the priority. If there’s a new service or product that we need, I’ll do the legwork myself and reach out to potential partners — or someone in our business development group will on our behalf.

I love that there are programs like CAS Future Leaders for graduate students and early career scientists. It’s an opportunity to shine a light on interesting work and showcase the diversity of talent in the next generation. But I’ve also never chased such awards myself, and have led a happy and productive career just the same.

Needleman’s Ten Commandments resonate true today, and delineate some of the value system differences between industry and academia that I wrote about further up in this blog post. I won’t go through all of the commandments here, but will highlight #10, which is my favorite: the world belongs to finishers.

One of the fine arts of discovering a clinical candidate is knowing when what you have is good enough. There’s an old saw that if you give a medicinal chemist infinite time, they’ll continue optimizing you toward an ever-better compound. An academic program gives you more time to explore the nooks and crannies of a chemotype and its pharmacology, but this is time that a successful pharma outfit cannot afford. You’ll never get a drug to market if you don’t stop tinkering, put your tools down, and evaluate what you have in clinical trials.

One good end that AI is being put toward these days is detecting shenanigans in images published in journal articles — duplications, transpositions, etc. Dr. Elisabeth Bik has made a career out of using her innate ability to see these duplications and taking people to task for it. Unfortunately, many publishers and editors are still a bit slow on the uptake, and the retractions — when they come — often lag the flagging of concerns by many years.

Given our increasingly fine-grained ability to detect low-level fraud, what on earth possesses people to think they’ll instead make up a really big lie and get away with it is beyond me. Extraordinary claims require extraordinary evidence, and are inevitably going to be tested by other people in other labs — most of whom, presumably, are not going to fake their results like the original report did. This is the check-and-balance by which science corrects itself, but we do ourselves no favors by just making shit up.

I like tiki-style drinks. Most folks think of rum-laden sweet fruit bombs when they think of tiki. While that’s true of many classics in the style, another defining feature of tiki is often a split base spirit — as here in this lovely and unusual interplay of bourbon and reposado tequila. But: tie it up with some cherry Heering for sweetness and a few dashes of bitters, and it’s magic. This one also contains no citrus, and can therefore be thought of as a stirred tiki-style drink — whereas most tiki drinks contain citrus and are shaken or blended. Another classic in the stirred tiki style that I love is the Conference, which is sometimes described as “a tiki drink masquerading as an Old Fashioned” — give it a try!

I’ll be sure to let y’all know when I collect my medical degree.