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Drug Industry History


I have an anniversary to celebrate this time of year: it’s now been thirty years since I started work in industrial drug discovery. Given the state of the industry over that time, just being able to say that at all has called for some luck and some flexibility along the way, but I’m very glad to still be at it.

What were the drug labs like in the fall of 1989? For equipment, I can think of two big differences: no column chromatography machines (prepacked columns, fraction detection), and no walkup LC/MS. There was nothing holding back the first of those, although if you’d shown me one during my graduate studies my mind would have reeled at such sybaritic luxury). But the lack of LC/MS is more understandable, considering that the electrospray technique had only been invented the year before by Fenn and co-workers. So yeah, what this means is that early on in my industrial career I still poured silica gel columns by hand and checked the fractions by TLC, but the clock was ticking on both of those tasks.

Another difference was that our NMRs didn’t even have sample handlers on them. Now, that was probably the company being cheap about it, because there was already one on the 300 Mhz machine in my graduate department by the time I left it. But we had the good old sign-up sheet, where you put your phone number down. And no, that was not a cell phone. Someone called you to tell you that they were finishing up their sample, so you went down and ran yours (you had a 15-minute time slot, in theory), and when you were done you checked the list and called the next lucky chemist. If I knew the next person well enough, I usually did that by saying “Get your worthless butt down here to the NMR, you hack” or something equally encouraging.

You got an automatic printout of the spectrum off an Apple LaserWriter at the end of your run; what you did not do was go back to your desk and work up the data on your computer. Because you didn’t have a computer. And that is the single biggest difference between the chemistry department of 1989 and the one of 2019, because at my first company the powers that be weren’t yet convinced that it was a good idea for people to have computers at all. The feeling apparently was that folks would sit at their desks and mess around with them rather than be out there in front of their fume hoods where they belonged – in fact, I heard that phrase almost word for word.

Nonetheless, within the next year or so, desktop computers began to make their appearance, at first shared between two or three people at a time. They were Mac IIci models; the head of our area was an Apple fan, and I was grateful for that, since it was Word and ChemDraw on a bunch of Mac SEs that had gotten me out of grad school a few years before. And that meant the introduction of e-mail, so I always have the option of appearing like a paleolithic hominid by telling people that I started working in the industry before we even used e-mail. We checked the darn mail slots instead – sheets of paper for memos, and those yellow envelopes with the little string closures for stuff that was more important or private. The string thingies saved wear and tear on our primitive flint hand axes, naturally (we used those to score the glass TLC plates instead). There was a manager who expressed a wish for pizza one day at a meeting, whereupon one of his reports walked down the street, bought him a slice, and then sent it to him in an interoffice mail envelope. But he was one of our more interesting specimens, admittedly, and the same dude who changed the network name, once we had a network, of the NMR room LaserWriter to “LaserWrither”, and no, it wasn’t me.

The whole lack-of-computers thing, and especially the lack-of-network thing, led to some situations. One of the biologists who’d been running assays for the first project I ever worked on retired in my first couple of years. It was only some time later that we caught up to the idea that he had (of course) been keeping up with all the assay data himself, on his own computer. With his own files, using his own FileMaker database, which now for some reason we could not find on his old machine, and there had been no particular provision for backing all this stuff up. So the call went out for everyone to search through their old hardcopy memos and meeting handouts to try to reconstruct as much of the information as we could. Even at the time I thought that this was clearly not the pinnacle of smooth data management.

The assays for the next project were cloned GPCR subtypes, and that was a pretty new thing, too. I came in just as the tissue-slice assays for those sorts of things were disappearing under the tide of molecular biology. Farewell possum trachea and rat vas deferens – some will recognize that this was a muscarinic project, and that neither of those examples are invented at all. The advent of pure cloned subtypes was greeted with some anticipation; we hoped that this would really settle things out, tell us key information about the new compounds, and make things move along faster and more surely. In reality, they did indeed help us to optimize against a particular subtype, to levels never seen before – but of course, the receptor assays did nothing to help out with most of the real problems with such a project. Such as the PK giving trouble as the compounds got decorated more and more baroquely to achieve that selectivity and potency (numbers that we really felt uncomfortable backtracking on). Or such as the fact that the whole project was aimed at Alzheimer’s in 1991 and was therefore doomed – that only became apparent later on. I also got to work on beta- and gamma-secretase before we even knew which enzymes those were, and you can guess how successfully that turned out.

Edit: of course, another big difference from that era was the way you searched the literature. I have waxed lyrical on this subject before, but don’t get the impression that I miss flipping through bound volumes of Chemical Abstracts, because yikes).

So that was the world of 1989 med-chem, and I hope I haven’t made it seem too distant. Because it wasn’t, in all the important ways: it was and is still a matter of skill and luck, of intuitive leaps and brute empirical experimentation, and the compounds still have to get made and get tested before you have any hope of knowing what’s going on. We use different equipment now, different instruments to play the music, but the song does indeed remain the same.

32 comments on “1989”

  1. Isidore says:

    I started working in industry a few years after you, and by that time email was more widely used and everyone of Scientist level and above had a desktop computer. But much else was still more-or-less as you describe it. One point regarding walk-up mass spectrometry: It wasn’t only that electrospray has really come into prominence very recently, it was also that it would take a few more years for hardware and software to become sufficiently robust to be used by the chemists in a reliable manner. In the mid-1990s I bought my company’s first “open access” LC-MS system for the chemists to check their own samples, monitor reactions and the like. At that time it cost something like $300k for an autosampler, a pump and a low-end single quad mass spectrometer. In today’s money this would be over $500k, which would buy you a medium-to-high end system with capabilities improved even more than, for example, in today’s PCs vs. 1990s PCs.

    1. Derek Lowe says:

      That’s just when I remember it coming into use, mid-1990s. And it was quite a change! I remember being struck by the amount of information I was getting from just one run, and that while I was off down the hall doing something else. It was clear immediately that the days of regular TLC plates were numbered.

      1. Anon says:

        @ Derek…….I started around the same period as you did. Personally, it had been a great run as a medicinal chemist and take pride in what I think as the “golden period” for a small molecule drug discovery. Despite adapting too many changes that were either self-imposed or imposed on us, it is my sincere belief that our triumph in terms of bringing medication from “bench top” to “bed” has more or less remained the same! Wish I could get some metrics on that? Because we had generated so much information, some relevant, others excessive, I reckon that we cluttered the scientific literature with enormous amount of data that is getting really hard to keep up with! In a way the olden times were better, I think! In terms of baseball analogy, I would like to think that our hit to run rate were much better, then.

  2. MattF says:

    The argument that higher management types made against desktop computers at the engineering lab where I worked was that they were secretarial tools. Which meant secretarial desks and secretarial chairs— both verboten for technical staff.

  3. Nick K says:

    The 80’s are a truly different era.

    Two other huge differences between then and now: the scale of the Chemistry, and literature searching. When I started (1986) we were enjoined to make at least 1g of the final product. Nowadays it’s a few milligrams. The company library still contained paper copies of Chemical Abstracts, which was always the starting point for any search.

    1. Derek Lowe says:

      Just added some links to past posts on that very subject – thanks!

  4. OldLabRat says:

    I started in pharma in 1988, so used printed Chem Abstracts. I feel that I learned a lot of chemistry while searching for synthesis routes. There was usually an interesting molecule in the next column or adjacent entry that pointed to new ideas. One other pre-computer note: the records for the company compound collection were kept on 4×6″ index cards in the Med Chem Directors office. One dropped off a request for a new compound ID; data for a melting point, IR, NMR, and an elemental analysis were mandatory. The slow part was the manual check for duplication of structure. A bit slower paced compared to the present day.

  5. mjs says:

    I still program in Fortran but at least the documentation is no longer in cuneiform on clay tablets.

  6. A Nonny Mouse says:

    As NMR auto samplers weren’t available in 1984, our company made their own which became the basis for the commercial ones. Sadly, the chemists had to use the old 60MHz machines for daily use (FT NMR was reserved for the phys chem experts who loaded the auto sampler- and only for test submitted samples).

    Additionally, in 1987-8 there were no drawing programmes for PCs, so one of the chemists wrote one (MoleDraw) which really came into its own with Windows 3 using cut and paste (before that it was print, cut out and stick in the report for copying). This gradually leaked through friends into other companies. Several companies wanted to launch it as a commercial product, but the company didn’t allow it (I see that you can still find it on the Web as well.

  7. Ir(bby) says:

    ok boomer

  8. Mister B. says:

    A point you may have not emphasize enough, is the data management. With less IT ressources, everything was slower, prone to error, data lost etc.

    Nowadays, we have so much ressources that we litteraly waste them. We generate terabytes of data that may not worth to keep and sometimes, I believe it clouds of judgement or the way me make decisions. (Especially with MedChem programs)

  9. Wavefunction says:

    Congratulations! At least you didn’t start in 1984.

    1. rnt says:

      Hey, I started in 1984! Made it to 2012 and then thankfully found a job in an academic institute. No fax, pc’s, and only internal emails back then. Smoking was still allowed and sometimes in meetings, the haze got really bad!

  10. MoMo says:

    You survived the Great Combichem Diversion too, Derek. I run into ex-combichem chemists, working at Home Depot or bussing tables, and they don’t look too good, so be sure to tip them well. The ones that are still employed grovel and apologize too much, but that’s what happens when you follow fads.

    The AI contingent will be the next wave of aging hardware and restaurant staff- and those that resisted and stayed in the lab will hopefully still be employed.

    Here’s to your next 30 years in Drug Discovery as slacker Gen Zs’ or other labels try to follow in our footsteps, without laboratory skills unless its a push-button. The smart will learn from us as we eventually die-off, the not so smart will parrot lines like “OK, Boomer”

    1. Derek Lowe says:

      Yeah, someone tried to recruit me into the Combichem Horde back in the day, but I demurred. It didn’t take all that long to see I’d made the right call, sadly.

      1. DNA libary says:

        The preferred term is DEL

    2. anon says:

      Jeez man have some sympathy for people who lost their jobs.

    3. Ok Bummer says:

      Don’t sprain your arm patting yourself on the back

    4. B says:

      Keep in mind in some of those times, the only jobs people could get was to follow those fads, especially if they are just out of school. If there is access, we do need to learn from those that came before us, especially if certain trends are repeating in various forms (combichem vs. DEL; comp. chem. vs. AI, etc.). Also appreciate the “cuneiform” comment from the person that knows FORTRAN;)

  11. Methyselah says:

    No CROs?
    No HTS? Often no hits for a good biological target
    No kinase inhibitors?
    No chemical biology?
    No high throughout in vitro functional screens?
    Secretive, indoor-centered organizations?
    Level of academic collaboration?
    No LLE?
    No PowerPoint?
    Smaller core Project teams?
    Scientifically robust leaders?

    1. Chrispy says:

      I remember going to my first Gordon Conference on Medicinal Chemistry in the 90’s and some clown from Novartis was getting ridiculed for the notion that you could make selective ATP-competitive kinase inhibitors. It was roundly seen as a fool’s errand.

  12. Scalliwag says:

    The bad news – you might not get a computer and have to spot your own TLC. The good news – you can graduate with a PhD and have your pick of big pharma jobs, signing bonus and all.

  13. Retro Sinner says:

    I started in discovery after a postdoc in late 1993, we shared a computer in the office and email followed about 2 years later. I did spend 6 months doing combichem but see it as a grounding in solid phase synthesis, the idea of de-optimising transformations was anathema to me. Now I live in process which I see as my natural home. Walk up LCMS has been a game changer but also the evolution of PAT in its various forms – whether IR , NMR, resistivity or whatever, making live observations can’t be beat. Also, back then, most people didn’t know what linking computers would really bring – people like Henry Rzepa at Imperial College had been thinking and looking into this for years but we’re hindered by technology from making a really big splash.

  14. Kling says:

    I tell the young and impressionable that I was doing molecular biology before PCR, when eventually reading 250 bases off a radioactive gel was one unit of hard work. They usually look at me as if I were some creature contemporaneous with Java man.

  15. enotty says:

    …worked on gramicidin lipid bilayer channel transport ~1984. Tried to infer MD from undergrad phys chem without solvent MD…

  16. An Old Chemist says:

    The intellectual property theft did not happen on today’s grand scale before the invent of internet, PDF, Powerpoint, and MS office.
    I started working in industry in 1987. In those days, we used to mail our resumes and cover letters by snail mail. I gave my interview seminars using Chemdraw files, as opposed to Powerpoint slides. Also, in those days, I used to have pertinent literature papers in manila folders lined up in my filing cabinets, as opposed to PDFs today.

    1. Jeff says:

      “Plagiarize, plagiarize, plagiarize… only be sure always to call it, please, ‘research’.”

      — Tom Lehrer, “Lobachevsky”, circa 1953

  17. Anon says:

    “We use different equipment now, different instruments to play the music, but the song does indeed remain the same.”

    This is why I think Pharma’s days are numbered: There is only so much you can do and discover by automating what we have always done, before the entire industry becomes commoditized and replaced by the next.

  18. Retired From BMS says:

    I started pharma in 1988, then retired a few years back when the company decided to exit diabetes and got rid of us all. This discussion brings back lots of memories, good, bad and in-between. Before the availability of desktop computers (yes, shared one per lab at the beginning, but better than in grad school where there was one computer for the entire biochemistry department, until my advisor got one for his lab shared with 11 people), I remember having to estimate Kms, EC50s, IC50s, etc. by hand graphing on semi-log graph paper and extrapolating. It was incredibly laborious and time consuming, but curiously rather in line with data from curve-fitting programs when they became available. By the way – “What’s the matter with kids these days; and get off my lawn!” ;>)

  19. Dan Schindler says:

    Down memory lane. I also started in November at Biogen in 1981 in offices in Harvard Square before Binney Street (now demolished) then Cambridge Center. Bob Fildes President

  20. PJP says:

    I started in Chemical Industry in1988 at a Fortune 20 company. At that point in time our group had a continuous wave 60MHz NMR with the vacuum table for the special NMR spectral paper. We mostly just checked reactions by setting blank paper on it and grabbing the pen and dragging it by hand through the spectrum….. Also, smoking still in offices. The big boss smoked cigars, which I did as well, he once threw me a cigar and we smoked it in his office and in the hallway. Very funny when I think about it.

  21. gnrhrules says:

    what about these paper notebooks with signature and witness requirement on each experiment? I had nightmare sometime because I can not locate my notebooks in my dream. Now it is no worry with enotebook.

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