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‘Tis Unfortunately the Season

Update: this post came just a few days before Teva announced that they’re starting a 14,000-job cutback, to run over the next two years. The season indeed.

Unfortunately, the Thanksgiving-to-Christmas season is a traditional one in the drug industry for layoffs and site closures. This is especially true for larger companies, who time these things more; smaller ones can hit the money wall at any time in the year. This is when (ten years ago) they announced that all our jobs at the Wonder Drug Factory were going away – not long before Thanksgiving, actually, just to make things more festive – and there are plenty of other examples.

Unfortunately, there are more. Eli Lilly doesn’t seem to have made an announcement about it, but it looks like they had a substantial headcount reduction in their Discovery Chemistry Research & Technologies department at the end of November. I’m told that there was about a 25% cut in that group at the Erl Wood site in the UK, and cuts in Indianapolis as well. This was presumably pursuant to this this earlier announcement in September.

And out in San Diego, Dart Neuroscience is closing entirely, with a letter from its founder stating:

“Despite the continued effort of an extraordinarily capable and dedicated team of scientists and the investment into research and development of well in excess of seven hundred million dollars, the company has not generated adequate signs of any human memory improvement or motor rehabilitation”

Who would have imagined that you could plow seven hundred million into neuroscience drug discovery and get no return? I mean, other than anyone who’s actually done any neuroscience drug discovery, that is. It’s not that I fault this as a business decision, but the strict business-decision mode would have probably mandated that you flee as quickly as possible from this area before putting money into it in the first place. Memory and cognition have vast unmet medical need, as they say, but as black-box therapeutic areas go they are matte, flat, stealth-bomber black. Dart will be closing as of February, which makes you wonder if this UCSD seminar series will have to be renamed.

66 comments on “‘Tis Unfortunately the Season”

  1. Anon says:

    That is what happens, when you do not know what is going on in a very difficult area, started by real estate company registered at Cayman Islands. Dart must be wondering as to why other major companies exited research in the neuroscience area? Or, he does not remember that!

  2. Emjeff says:

    “Who would have imagined that you could plow seven hundred million into neuroscience drug discovery and get no return? I mean, other than anyone who’s actually done any neuroscience drug discovery, that is.”

    This statement should be carved in marble and put in every biotech center in the country.

    1. Joe Hedrick says:

      Actually you can just leave out “neuroscience” and that would work very well

    2. Mark Thorson says:

      Quincy Biosciences seems to be doing quite well on their neuroscience memory drug originally found in jellyfish. I rather doubt they spent anywhere near $700M developing it.

      1. Pennpenn says:

        Well that’s great for them. Still doesn’t change the fact that you can throw a lot of money into drug discovery black holes and not even get back the radiation discharges back regardless of your goals or intentions.

        1. immunoldoc says:

          Do a search on Quincy Biosciences…I think you will not be impressed

      2. Derek Lowe says:

        The only problem is that it doesn’t actually seem to work.

        1. oldnuke says:

          Details, details, details. I wonder if the jellyfish they mention as the origin of their “wonder drug” are actually referring to the investors? 🙂

          Elephants might be a better source, as they never forget!

      3. Terry says:

        I worked across the bench (as a bachelor thesis student) from Osamu Shimomura in Frank Johnson’s lab at Princeton while the aequorin/GFP discoveries were made (40+ years ago). It makes me so angry that these idiots (Quincy fraudsters) are trying to profit off apoaequorin as a supplement based only on the Ca++ detection as used long ago in mapping neuronal ion flux.
        While I worked on bacterial luminescence/carbamate inhibition, I still poured a few columns and watched GFP migrate under a blacklight in the evenings while my reactions were running. Osamu, his wife, and Frank were the epitomes of class acts in science, and it’s a shame Frank died before the 2007 Nobels, or he could have had a share.

  3. luysii says:

    Chemistry is sorely needed by the people doing neuroscience research. The following is a direct quote from the current issue of one of the most prestigious neuroscience journals Neuron [ Neuron vol. 96 pp. 680 – 696 ’17b ] http://www.cell.com/neuron/fulltext/S0896-6273(17)30935-2.

    “A consistent prediction across models is that the glutamate concentration profile reaches a very high peak (over 1 milliMolar), but only for a brief time period (100 milliSeconds) and over a small distance (100 nanoMeters).”

    Glutamate (glutamic acid) is the major excitatory neurotransmitter in the CNS.

    Models are lovely, but how many molecules of glutamic acid are they talking about? It’s easy (but tedious) to figure this out.

    We know the volume they are talking about: a cylinder 100 nanoMeters in diameter and 40 nanoMeters tall (the width of the synaptic cleft). So it contains pi * 100 * 40 = 12,566 cubic nanometers –round this down to 10^4 cubic nanoMeters. A liter is a cube .1 meters (10 centimeters) on a side. So 10 centimeters is 10^8 nanoMeters, meaning that a liter contains (10^8)^3 = 10^24 cubic nanoMeters.

    A 1 molar solution of anything contains 6 * 10^23 molecules per liter (Avogadro’s number), so a 1 milliMolar solution (of glutamate in this case) contains 6 * 10^20 molecules/liter or 6 * 10^-4 molecules per cubic nanoMeter. Multiply this by the volume of the cylinder and you get a grand total of 6 molecules of glutamic acid in the cylinder.

    If I’ve done the calculations correctly (and I think I have), “a very high peak (over 1 milliMolar)” is basically scientific garbage, the concept of concentration being stretched far beyond its range of meaningful applicability.

    I’d love to stand corrected if my calculations are incorrect. Just make a comment.

    1. anon says:

      “Chemistry is sorely needed by the people doing neuroscience research,” but Chemistry and chemist are treated like crap, if you take a look at the salary at a post-doctoral level! The millennials are not interested in chemistry, and meanwhile they got rid of people who really love chemistry.

    2. AF says:

      Unfortunately a lot of people in the biology, medical and biomedical fields do not understand the necessity of being quantitative …
      I have lost 10 years on things like this …

    3. APAJ says:

      “We know the volume they are talking about: a cylinder 100 nanoMeters in diameter and 40 nanoMeters tall (the width of the synaptic cleft). So it contains pi * 100 * 40 = 12,566 cubic nanometers –round this down to 10^4 cubic nanoMeters.”
      Just one err in the maths: the volume is r^2*pi*h so it’s closer to 3^5 cubic nm. This leads to ~188 glumate molecules following your further calculations. A more significant number, but I agree concentrations should not be used in these kind of volumes.

      1. luysii says:

        APAJ — Thanks — you’re correct and I’m embarrassed — pi * diameter is circumference not volume. so its pi * 50^2 * 40 = 314,259 cubic microns == 25 x more than 12,566 bringing the number of glutamic acids up to 150 (when 12,566 is rounded down to 10^4).

        But we’re not talking about a solution of glutamic acid in water — the article discusses the large numbers of the many different proteins found in the synaptic cleft and their orientation. For more on this please see — https://luysii.wordpress.com/2017/12/10/the-flying-wallendas-of-the-synapse/ which discusses the whole article.

        1. APAJ says:

          Ah, and then the Introduction to Chemical Thermodynamics classes come back to haunt. Concentrations? Not relevant! We need the activities of species. Not to mention the various assumptions about ‘bulk’ water, the presence of chaperones or other binders, solvation shells.. ‘Life’ is truly complicated…

          1. luysii says:

            Activities indeed. I long ago left chemistry, but keep up with friends who’ve stayed in. Back in the day we used to refer to DeBye Huckel theory as applicable to slightly contaminated distilled water. Activities were regarded as fudge factors to make the thermodynamic equations come out right. Back then they were experimentally determined, not calculated from first principles. I asked an old friend who has just retired as a chemistry department chair, if this was still true of DH theory and activities and he said that it was.

      2. Kevin H says:

        Speaking naively, I would note that having a concentration* of 1 mM and heaping scorn on the authors because it’s only 188 molecules could be unfair. The authors mention a “brief” time period of around 100 ms, but on these length scales, a few milliseconds is a relative eternity (ask anyone who does molecular dynamics simulations).

        Having 188 molecules of glutamate in the synapse doesn’t sound very impressive, until you ask–is it the same 188 molecules for the entire 100 milliseconds? How long does it take for a glutamate ion to diffuse across the tiny volume, and bind to a target on the other side? How many of them will be able to make the trip in 100 milliseconds, even if only a couple of hundred are “in transit” at any particular instant?

        If it takes 100 microseconds (very rough order-of-magnitude number) for a glutamate ion to migrate/diffuse/bounce its way across or out of the modelled volume, then you’re going to need to “refill” the box 1000 times in order to maintain the concentration. Now we’re taking about a couple of hundred thousand molecules, not 188….

        *(And yes, I agree that trying to talk about “concentration” when you’re in a volume where you can plausibly count individual molecules is stretching a lot of the underlying assumptions we usually make about the concept….)

        1. luysii says:

          More apologies — I misquoted the article — it is 100 MICROseconds, not milliSeconds. One more mistake and it’s time for a nursing home.

          1. Ab says:

            luysii… here’s an opportunity to redeem yourself.
            Can an antibody fit in the synaptic space? (assuming all proteins linking the pre- and post-synaptic space are not there…)
            Thanks…

          2. luysii says:

            The width of the synaptic space is cited as less than 40 nanoMeters (400 Angstroms), so all the immunoglobulins (including IgM) should fit if oriented correctly as long the width is greater than 100 Angstroms. Most electron micrographs of synapses show larger widths than this.

    4. Bla bla says:

      At least we know how to report experimental values. So many times you just see a value (yield etc) as a single number. N? SD? SEM? Completely meaningless.

    5. anon says:

      concentration and amount are two separate concepts. the electrons passing thru the elctrodes used to stimulate the neurons are also very a few yet you dont like to be electrocuted.

  4. anon says:

    Used to think animal models in Immunology suck (wait….they do, actually) but models for depression/schizophrenia/memory/pain are substantially worse. PK, affinity/potency, CNS availability, reasonable hypothesis, target engagement in Ph1? Just roll the dice in the clinic- it will likely fail but you will have saved time & $$

    1. steve says:

      Actually, it turns out that immunology models in mice do not suck and many are predictive (e.g., anti-TNF treatments for RA). What’s interesting is that the mouse immune system is actually quite like the human. The problem is that researchers keep mice in sterile environments and as a result their immune systems are quite immature. If you look at field mice they very much resemble humans. Take a look at the work by David Masopust at Univ Minn.

      1. anon says:

        …or try to do animal models when pollen counts are high (affects RA models), or handle the mice too much (shows efficacy in mouse model of MS), or do models in out-bred animals (sorry, we can only run that model in C57Bl6 purchased from Jackson labs…), ….etc. Mouse (rat?) models of inflammation/immunology are very neutrophil driven-is this the case in human diseases of interest in the therapy area i.e. RA, MS, IBD, …? BTW- anti-TNF-a worked gangbusters in mouse MS; exacerbated MS in patients.

        PS- really not trying to pick on in vivo folks. Ph1/2 trials often don’t predict efficacy in Ph3-

  5. Electrochemist says:

    All told, Lilly is exiting around 45,000 of experience during the month of December. Sad!

    1. Electrochemist says:

      “45,000 years of experience, I meant”

  6. Darttruth says:

    They hired people that came from Arqule (fraudulently claimed they “automated” chemistry when it was nothing more than a custom synthesis shop) to head up med chem research.

    Dart never was a serious effort.

    1. Rammstein says:

      Curiously, there is a paper in just accepted’ Org Proc Res and dev from Dart NeuroScience. It appeared today 12th.

    2. Dart alternative fact says:

      The head of discovery chemistry had previously worked at BMS, Axys, and J&J.

  7. Chrispy says:

    Dear colleagues in this industry:

    You simply have to accept that layoffs and site closures are part of this career. No matter what assurances you get to the contrary, you can rely on unplanned vacations in your future. “Ah,” you may think, “but I have especial talent, our division was picked as a center of excellence, and I have chart-topping reviews for the past few years.” Do not be a fool. That is not the way this business works, and cutting research remains an easy target for making a company more profitable, at least in the short term.

    If you want to keep your sanity, there are a few things you need to do:
    1) Save money. These jobs tend to pay well while they last, but you need to live well below your means and accumulate. This may be the single most important thing.
    2) Publish and network. Some places discourage publication, but it is really critical in this era that scientists get their work out there and get a reputation that extends beyond their employer. Talk at conventions. Keep in touch with old colleagues.
    3) Find a sense of self-worth outside of your job. Perhaps this is family, volunteer work, or even hobbies. Many scientists find themselves with a soul-crushing sense of inadequacy when laid off, having devoted so much of their lives to the pursuit of a particular profession. I have observed many colleagues who suffer symptoms of PTSD even years after getting laid off and years into a new position.

    Finally, for those of you “lucky” enough to avoid the axe when it swings, stay in touch with people who were let go. It is not uncommon for laid off people to feel like pariahs among those still employed. “Blame the victim” is a survival strategy for companies who lay off staff, and the remaining staff can often be found to adopt the same strategy at a personal level. Do not let a company corrupt you in this way.

    1. Marcin says:

      … and if you did not graduate from a top university and/or did not work for one of big pharmas – start considering an alternative career. Saving will become crucial!

      1. Nominal says:

        I know I’ll be ok, I passed my masters with the ‘D’ and my advisor will write me a great letter if I ever get laid off.

      1. NMH says:

        The problem is, even though you should not judge yourself harshly for losing a job and not having a lot of net worth, many others, especially close to you, may not be so kind…..

    2. cynical1 says:

      Chrispy: Sage and sound advice. Your 3 points could not be more true and your last point was very well spoken.

    3. Derek Lowe says:

      Solid advice at all levels, I have to say.

    4. bookdabook says:

      Dude, so right! Full disclosure, I am one of the DNS alumni. The work we do can be a lot of fun but shut downs are part of the game. So enjoy the job while you have it and have fun with the like-minded people around you. Hopefully most of the people affected by this shut down will get back in the game in some way.

  8. Uncle Al says:

    What lab ever generated revenue? Disappear your R&D. Costs drop, profits are unharmed.

    “Make an 80 wt-% water hydrogel, Plexiglas refractive index, silicone rubber physicals” (re low RI fragile Sauflon). Hydrated Invulneron simultaneously stretched 100% in perpendicular directions and was hella refractive. I blew its first vacuum polymerization ampoule from a cheap test tube and a Dispo-pipette. I still have samples inside fried Pyrex USA No.9800 white logos

    Nothing, not even a DK/t measurement (therefore, zero risk).

  9. David Edwards says:

    Apparently it’s not all bad news in the world of neuromedicine.

    I just alighted upon this.

    A chink in the armour of Huntington’s has been found. The initial results are reported to exceed expectations. Not quite champagne cork popping time, but this is a development I never thought I would live to see.

    Quite simply, this is the sort of news that takes my breath away, at what we as a species can achieve if we put our minds to it. I used to think Huntington’s was just too hard a nut to crack for the foreseeable future, then this news appears.

    I suspect Derek will want to delve into this one a lot more, and write a post on the subject, but right now, to my admittedly untrained eyes, this is serious good news.

  10. shanedorf says:

    We all contributed to DART’s coffers in that they were the inventors of the ubiquitous SOLO cups. Red or blue plastic with measuring lines molded into them to denote 1 shot, 4 oz, 12 oz or 16 oz. Those cups were the source of funding for the DART empire, including their foray into drug development. Noble use of the cash we all spent putting ethanol into our systems…

  11. Zara says:

    Thanks for your article, Derek, and for your comment, Chrispy. I know dedicated, talented scientists at Dart, and wish them all the best.

  12. Insilicoconsulting says:

    It’s a given the drug discovery is VERY hard pursuit and often a fruitless one. Yet, I find it strange that one the one hand people criticize tech companies of using up intellectual abilities in selling stuff or in social media pursuits etc and not investing in “real” science. And here we have someone from a real estate background who actually invested 700 mUSD in neuroscience, generated jobs etc. Regardless of how difficult the field is where the people were recruited from, why the snide remarks about why didn’t treads where Angels fear to?

    Or would you rather have him starting another Uber, Alibaba, facebook? Does he have a tainted history or tainted money that he was trying to launder? Or was he motivated by some personal story?
    This is exactly the kind of attitude that undermines good intentions.

    1. Nicky says:

      While I agree with your first points, Kenneth Dart has a storied history of questionable ethical business ventures. His holding company deals in vulture funds, buying debts at fractions of their value from countries who are nearly bankrupt, so they can delay defaulting on debts, and forcing said government to pay them back in full on later dates. A man who made over a bn USD off the Greek and Brazilian financial crisis makes me feel icky.

      To further salt the soup, he also renounced his US citizenship in favour of Caymanian citizenship to dodge the IRS. He’s offshored a ton of his real estate assets to the Caymans. When I lived in the Cayman islands for a short while for non-chemistry related work, he was a big name and I heard about him quite a bit

      1. DCRogers says:

        Well, Andrew Carnegie wasn’t known for his ethical business practices, but we still appreciate him using much of his however-gotten-gains to fund libraries and schools.

        I wish more of these modern billionaires would toss a gamble into funding drug development!

      2. Design Monkey says:

        > A man who made over a bn USD off the Greek

        Actually, Greeks helluva deserved not only that, but way more. That’s a country, which is total national financial fraud for 40 years already. EU unfortunately is still pussyfooting with them, Greece should have been kicked out of EU years ago.

    2. Derek Lowe says:

      I have to say, you have a point. I definitely appreciate the likes of Dart putting money into this business, but I guess I’m startled at his expectations of earning a return in that particular area.

      1. bookdabook says:

        DNS alumni here again. Yes I would have to say, >700M, is a pretty badass investment from an aging billionaire looking to hang onto his memory. Having met him personally, he is a very modest, somewhat nerdy, skinny quiet guy whose favorite shoes are all black converse tennis shoes. I would bet if left up to him alone, he would have spent much much more willingly. DNS had queued up many trials in multiple therapeutic areas and had just lined up access to a major senior population center. However, I suspect some people in his Cayman boardroom have had a big number 7 on their whiteboard for quite some time now. So business is business and we’ll have to wait a little longer for the next great memory drug.

  13. Anonymous says:

    “Who would have imagined that you could plow seven hundred million into neuroscience drug discovery and get no return?” Cambridge (MA, not UK) NeuroScience (CNSI) had some of the highest paid leadership in Boston Biotech for over a decade. I’m not sure what they discovered after spending a ton of money in the 1990s, maybe more than $700 MM in 2017 dollars. Well, they probably discovered the same thing that Dart discovered, but 15-20 years earlier! They also discovered that you can still get plenty rich in the front office of a well-funded biotech regardless of the scientific outcomes, without any accountability.

    1. Emjeff says:

      One of the things I’ve learned working in small pharma is that many people start these companies as a way to “steal small”. It’s easy for the feds to catch you if you embezzle or commit stock fraud, but if you raise capital to fund a start-up, hire people to do some work and (and this is the important part) pay yourself a big salary and give yourself stock options, you can effectively steal millions and never get caught. You need a board of directors to be in on it with you, but that isn’t difficult, since they are stealing as well (by being paid a ridiculous amount of money to go to four meetings a year and also getting options). It goes on all the time.

      I got into this industry because I thought I could help people. That happens (occasionally), but I’ve realized that there are a lot of shitty people in this industry that are just in it to make some quick cash. To say that I am disillusioned is a huge understatement.

      1. AF says:

        A lot of people selling the Brooklyn bridge …

      2. anon for this one says:

        I used to work with a few guys who left a biotech startup. They admitted to me that everyone there did nothing but play computer games all day, the owner was great at writing grant proposals, and the whole thing was pretty much a scam.

      3. Isidore says:

        Of course stock options for a CEO or BoD members are worthless unless the company does something worthwhile to justify going public or being bought by someone, and for either of these things to happen some work needs to get done and results produced.

        1. tangent says:

          Maybe the SEC could require that if you’re going to raise money from investors, you (the CEO and big mucketymucks) don’t get to pay yourself a rich salary — you have to take it in ownership stake.

          (Sure, the CEO can put a friend in at a high salary and take half of it under the table, but it’s easier to catch “dude is using money he never declared as income.”)

  14. Pharmawhore says:

    Thank God for Bitcoin!

  15. The millennials are not interested in chemistry, and meanwhile they got rid of people who really love chemistry.

    1. Erl Wooder says:

      Well that’s a pretty crap statement.

      (I could say, in my experience the fossils are more interested in creating politics and drama than chemistry. )

      1. Disgruntled Medicinal Chemist says:

        This, many many many many times over.

      2. Annoned says:

        People who are mostly politicians and dramatists survive because they use a lot of politics and drama, not because they are fossils. I know because I became one of the dinosaurs that did not survive.

  16. The problem is, even though you should not judge yourself harshly for losing a job and not having a lot of net worth, many others, especially close to you, may not be so kind….

  17. Arnob Endry says:

    Models are lovely, but how many molecules of glutamic acid are they talking about? It’s easy (but tedious) to figure this ou

  18. IhaveafriendinTeva says:

    Teva is going to cut about 14,000 jobs and close one U.S site among others in other countries.

    https://www.biospace.com/article/unique-it-s-official-teva-cuts-14-000-jobs-in-massive-reorg/

  19. Phuck Pharma says:

    Time to just quit this industry, move to Thailand and have sex with ladyboys!

  20. David Edwards says:

    From one of the comments above …

    “… shows efficacy in mouse model of MS …”

    Do you have a paper covering this I can read? Only if there’s a measurable effect from handling MS model mice, I’d like to know a LOT more about this!

  21. Pharma Joe says:

    Word on the street is that the ex-Dart employees received one year of severance along with health benefits which leads me to believe that it wasn’t about the money in the end but rather the outcome of the research data. Holy cow! I wish I worked for a biotech company like that. That’s unheard of in any industry let alone the biotech/pharma area.

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