About this Author
College chemistry, 1983
The 2002 Model
After 10 years of blogging. . .
Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: email@example.com
December 21, 2007
It’s time, across most of the drug industry, for people to prepare their labs for a few days off. Some companies officially close between Christmas and New Year’s. At the others, you’ll find about 20% occupancy, and those people will likely as not be taking advantage of the time to shovel stuff out of their offices. Not much drug discovery lab work gets done in the last week of December, I can tell you.
I’ve written before about how I used to leave my lab space in what I thought was good shape, only to come back after the break and find that I’d labeled flasks with helpful legends such as “Large Batch” or “2nd Run”. And every January, there I’d be, looking at some tan-colored stuff and thinking “Hmm. Second run of what, exactly?” I could usually work it out, but a couple of times over the years I’ve had to run NMR or mass spectra just to figure out what I was getting at.
So, make sure your stuff is labeled with something more intelligent, is my advice. And even more importantly, make notes to remember lines of research, and plans of what to do. It’s easy to lost the thread after being off for a while. This isn’t always bad – one of the good things about a break is that you lose the threads of a few things that are well lost. But it’s a good idea to write down what’s in progress, what you plan to do about it, and what you’re going to try to do next.
I’m convinced that a lot of good ideas get lost. They're not followed up on, they're forgotten, or they're buried under later duties. I've been trying to keep that from happening, which is one reason I was asking about literature and note-organizing software a while ago (more on that in January). One of my tasks today is making sure that all the current thoughts I have are battened down for the season. As usual, it'll probably turn out that some of the things I'm doing now would be well replaced by some of the things I've just been thinking about.
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December 20, 2007
No real post today - too much snow shoveling, etc. Things will be a bit irregular around here during the holiday season, as usual, and I think that today will kick it off.
People have asked me how I'm liking Cambridge now that I've been up here a few months. The answer is, just fine. This Christmas season is a great improvement over last year's, that's for sure. Mind you, right now we've got between two and three feet of snow on the ground out here to the west of town, and my wife and I have taken a couple of unplanned sled rides down our steep driveway, with a Honda Accord substituting for the traditional sled.
And although I've spent the last twenty years moving to higher and higher latitudes, I have yet, it seems, made it far enough North to where traffic doesn't go to pieces when it snows. I take the train myself, which works out fine, but last Thursday people were taking hours just to get across Cambridge. (That's as opposed to a weekday morning, where those three miles only take 45 minutes - I did say I was taking the train in. . .)
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December 19, 2007
There is a pecking order in chemistry. That’s because there’s one everywhere. If it’s a human endeavor, staffed by humans, you’re going to have hierarchies, real and perceived - who you did a post-doc with, what huge company you're a big wheel in. But that doesn’t mean that we have to bow down to them, and it doesn’t excuse this sort of thing, from The Chem Blog:
” Waaaaaayyy back at the ACS in San Fran at the poster session, we were walking around and introduced ourselves to this guy standing in front of his poster. Now… old boy (a graduate student) engaged us in some dialog about his poster and we were getting along famously, my friend asking most of the intelligent questions (I was still recovering from giving blood a few hours before and drinking multiple beers immediately after.) As conversations normally flow, he asked us where we were from. I told him my fine institution and my buddy told him his. I assume he wasn’t put off my by school, but the look on his face when my buddy told him where he was from was at first a “are you serious” chuckle, which melted into one of those “do they have a department” and finally to a resound(ing), “I’m done with you.”
I stood there and watched it the whole time. So, my buddy being naive to the ways of the world, kept asking questions but the answers weren’t forthcoming any more. In fact, in the midst of a question my buddy was asking, the guy actually walked away from his poster and started talking to his friends. . .”
Read the rest of the post for the rest of the story, which goes off in a different (and still interesting) direction. But as for this behavior, there’s just no call for it. As far as I’m concerned, if a person is asking intelligent questions, they’ve already provided all the credentials they need to show. Likewise, I reserve the right to discriminate against time-wasting bozos (just as I reserve the right to define that class, although I’ll bet that most of my picks would easily pass a show of hands). But if you’re presenting a poster, you have, whether you realize it or not, entered into an agreement to take on the broad unwashed masses.
Tactfully dealing with the clueless is a learned skill, but no such skill seems to have been called on here. This is tactfully dealing with the intelligent and informed, and if you can’t do that, you have some serious problems. It takes an awful lot of red-hot results to make up for a really obnoxious attitude, and a degree from Big Name U is only partially going to offset one as thick as this. Now, it's true that there are certainly some pretty abrasive folks from BNU, but the ones with the proven big-time track records can at least get away with it. Too many other morons take the shortcut, deciding that the nasty attitude is some sort of essential first step – in some cases, deciding that it and the Big Name is all they need.
Out here in the real world, where Poster Boy has yet to tread, it becomes clear that the wonderfulness of a marquee school background eventually goes stale. There are places in the drug industry where working for particular academic bosses will give you a leg up – for a while. It’s a real advantage to be able to get in the door that way, no doubt, but once you’re through the door you generally have to produce something. (And it’s good to keep in mind that even these advantages don’t necessarily last forever. A rollicking management purge can destabilize an old-boy network very quickly).
No, doing lots of work and doing it really well is a better long-term strategy. (Another part of that strategy is to make sure that people know who’s doing it, but that's a topic for another day). And having a personality that makes people grit their teeth and wait for you to leave is not such a good long-term plan. I wish Poster Boy well, but I hope that he has a lot to talk about. This isn't one of those businesses where you can get by on looks.
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December 18, 2007
The next few years don’t necessarily look good for several large drug companies, just because of the patents that will be expiring. King of them all is Lipitor, of course, the world’s biggest selling drug which will then become the drug industry’s single largest lost revenue stream. But if you dig back through the newspaper archives, you’ll find the “Big Patent Expirations Looming” story showing up year after year. It’s basically true every time.
And that illustrates a point that a lot of people from outside the drug industry forget when discussing our rapacious business models, obscene profits, and so on: more than almost any other industry, we’re built on a pile of wasting assets. And not just any old nonspecific wasting assets – our valuable drugs are ticking away with a specific timetable, at which time they turn generic and most of the revenue stream goes flooosh. There might as well be a big LED clock strapped to the things, counting backwards – but unlike a bad movie, there’s no sweating hero trying to figure out whether to cut the red wire or not. Put down those needlenose pliers, Buck or Jock or whatever your heroic name is, because nothing will help.
Nothing, that is, except having some other drugs coming down the chute to replace the ones that are blowing up. Oh, I know, I know, patent evergreening and so on. I agree that it’s a problem, but that stuff doesn’t work most of the time. And when it does, you can maybe wring a year or two out of the system. But the bells toll for all our drugs in the end, and we have to deal with that fact by cranking out new stuff as fast as we can.
In recent years, that hasn’t been fast enough. I worked for a company back in the early 1990s that had a big-selling drug which was headed for the patent cliff. Everyone knew it, everyone knew when it would happen, and everyone knew what we had to do about it: get more stuff into the pipeline to replace it. The company expanded its research department and built a whole new drug discovery building complex to put us all in. To no avail. The day came, and nothing significant had been found in the intervening years. The company’s earnings hopped into a handy handbasket and went to the usual destination, the stock fell off a cliff, and all sorts of people who’d been loading up on the shares during the glory years felt all kinds of pain.
This story has been repeated several times around the industry. We all know about the declining productivity story – it was one of the first things I blogged about back in 2002. But the back side of that story is the frantic activities to try to make it go away. Some of them aren’t too glorious – cherry-flavored line extensions, patent gimmickry – but a lot of the work is serious stuff. We know that our discovery and clinical success rates are too low, and we’re pouring all kinds of money into trying to fix them. So far, the successes haven’t been anything to jump around about, but the efforts continue.
There’s an exception: the biotechs. The FDA has been trying to get its regulatory head around the issue of biogeneric equivalency, but it isn’t easy (more on this in a separate post some time). What this means is that the likes of Amgen, Biogen, Genentech Genzyme et al. have had far fewer worries about some of their products expiring on them. If the FDA can’t certify that a generic version of a protein drug is the same as the original, and can’t agree on how to even do that in the first place, then no generic will appear. There are several companies that would like to do it, but they’ve been moving more slowly than they’d like to, since the regulatory environment is so unclear. Things are moving a bit more quickly in Europe, but the pace is still glacial compared to the situation over here in the traditional small-molecule world.
And that’s not doing the biotech industry any good. I realize that this sounds perverse, especially to the people at the companies involved. What do I mean, that it’s a bad thing that their drugs rake in billions year after year? What’s not to like? Well, what’s not to like is that this kind of thing slows down the need to come up with new products and new approaches. I know that the big biotechs are spending lots of money on research, but we’ll never know what things would have been like if the dogs had been at their heels more. Organizations get lazy in all kinds of almost imperceptible ways when there’s no reason to move quickly.
Having those incentives doesn’t mean that things will work out for you, of course – see that story a couple of paragraphs above. But I think it works out better for everyone if research organizations are kept on their toes, competing with each other, and competing with those big red digital countdowns. It’s no fun, but it’s the best way.
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December 17, 2007
There are plenty of chemical reagents and reactions that go in and out of fashion over the years, and even entire elements. For the last couple of years, it’s been gold – ten years ago, gold-catalyzed reactions were a backwater, and now they’re all over the literature. (Catalysts are the way to go; reactions that need excess gold to run are unlikely to catch on). Hardly an issue of Organic Letters goes by these days without some gold-catalyzed cyclization in it. But there are some elements that have never been in fashion, and odds are that they’re never going to be.
Tellurium comes to mind. It does some interesting reactions, and if it wasn’t rather poisonous and if its compounds didn’t stink beyond the ability of anyone to stand them, I’m sure that we would have discovered even more. But it is and they do, and there’s no way to stop either one, so no one’s going to make the effort any time soon. It’s the stench that really seals the deal, actually. Poisonous we work with all the time, but you don’t come across stuff that smells like organotelluriums very often, or so I hear. I’ve never had the pleasure myself.
And as for lab fashions, it’s also safe to say the day of the heavy metals is past. Mercury has a long, long pedigree in both organic and inorganic chemistry – back to the alchemists, actually. Everyone figured that there must be something special and/or magical about a metal that’s liquid at room temperature. They were right, in a way. Mercury does a lot of interesting reactions which are still taught in sophomore organic classes and are still run once in a while. I’ve done a few organomercurations myself, but most of them were years ago in grad school. I’ve only reached for the mercuric chloride once or twice in the last twenty years. That’s doubtless because I’m in the drug industry, but I think that the general use of the element has been trending down because of waste disposal issues. Lead, for its part, never had as much use in the art as mercury, and will probably never get the chance.
It’s not just the heavy metals, either. Beryllium is probably one of the most underused elements in the whole periodic table, as far as organic chemistry is concerned. Considering its spot up near the light end of the periodic table, where all its neighbors are on every lab shelf, you’d think that there’d at least be something you could do with the stuff. But I can’t think of a single reaction I’ve ever seen that uses it. The element’s peculiar toxicity (which mostly seems to be a problem by inhalation) helps keep it out of the spotlight: no organic chemist has ever found a need for it that outweighs its disadvantages, and not many are motivated to try.
None of these are going to be the next hot thing. But what is? Gold’s turn in the organic chemistry spotlight will end at some point – for all I know, things are already slowing down. If I had to guess, I’d pick another candidate from the precious-metal crowd, and I’ll nominate iridium. There are plenty of iridium-based catalysts, but none of them are the absolute first thing a chemist reaches for. It wouldn’t surprise me a bit if the element turned out to have a number of tricks in it that haven’t been discovered yet. They should at least be worth some JACS and Org Lett papers, that’s for sure. . .
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December 14, 2007
So a month after putting itself on the market, Biogen Idec has decided to take itself back off. This is, I’d say, good news for the company’s employees, since many of them stood to be redundant after a sale. That would especially apply to the company’s medicinal chemists, because even though they have some good people there, anyone buying Biogen probably isn’t interested in their small-molecule expertise.
And I think it’s good news for the biotech industry in general. I think any industry benefits from having a lot of firms competing with each other, trying different ideas and approaches, and keeping each other on their toes in the areas where they overlap. A big consolidation in the biotech field would cut down on what we might as well call its genetic diversity, at least until new companies sprang up with their own ideas.
For whom is this bad news? Well, for starters, how about people who bought into the stock at the elevated levels of the last couple of months? Somebody was holding that bag when the news broke last night, and they must have realized that this would be one of those days. BIIB had been trading at about $75 the day before. It opened at around $54, and staggered in at $58. It's now back to slightly below where it was trading before this whole thrill ride started - but at the height of the takeover talk back in October, it broke $80 for a bit. So, the first paragraph of this blog aside, there must have been a lot of Biogen employees holding company stock and options who got burned yesterday. I hope some of them sold over the past few weeks.
Today’s deflation is also bad news for anyone who stepped into some of the other speculative biotech stocks (Genzyme, for example, down today). You can be sure that the usual suitors (led by Pfizer) looked over this deal and some of the others carefully, fingered their wallets, and thought better of the whole thing. That has to make you wonder if some of the other buyout candidates should be commanding the prices that they’ve been. BIIB has the complication that its largest drugs are also tied up in outside collaborations, making the whole takeover idea more expensive, but still. . .
How about Carl Icahn? I assume that he was hedged against this sort of thing – it would be interesting to see how many put option contracts were open on the stock, for example, or what the short interest was. Icahn and his people have surely been doing this sort of thing way too long to get caught too badly when a potential deal falls through. And if he was really sure that the company was undervalued, hey, now’s the time to pick up some more shares.
So, now we wait until the next round of speculation. Many of the large companies in the industry still probably need to shore up their portfolios, and we’ll surely have a recurrence of Merger and Acquisition fever. And that brings up another set of people that are unhappy about todays’s news: the investment bankers. All those fees. . .those fees. . .they just evaporated. My condolences, guys. Right.
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December 13, 2007
I've written before about some elements and functional groups that don’t exist, but which I want anyway. Today I write in praise of triple bonds, and with the forlorn hope that they could do more. The thing about triple bonds is that they’re straight, the steel spacer bars of the chemist’s building set. Every type of bond has its characteristic angle, and for this one it’s 180 degrees. There’s nothing else like it.
Let’s take on the CN case first. I need something like a nitrile that’s not metabolically labile. There’s nothing like CN – it’s polarized because of the nitrogen, and the triple bond just sort of pokes that charge out there. No other functional group is an exact mimic. But the weakness of the triple bond is that it’s a bit precarious, energetically. Piling up those bonds buys you less and less stability as you go, so there’s quite a bit of energy to be sprung. (That’s why the simplest CC alkyne, acetylene, is such an energetic fuel). In the case of the nitrile, it can be torn up by the liver. Although it sometimes escapes, it’s always under suspicion.
And there’s another problem: its electron-withdrawing means that if you put it on an alkyl carbon it generally makes any hydrogens next to it too labile, so most of the ones you do see are on aromatic rings. And there’s another minor problem with the alkyl cases: if you put a CN anywhere that it can act as a leaving group, you run the risk of giving off the nitrile’s evil twin, negatively charged cyanide ion. Yep, a rock-solid, nonreactive nitrile group would be a big hit. Note to self: get cracking on that one.
While I’m at it, I want to tighten up those alkynes. C-C triple bonds show up sometimes in drugs, but they’re show up a lot more if we weren’t worried about them getting metabolized. You can get some interesting molecular shapes by putting in an alkyne, but the liver loves to oxidize them, especially if they're sitting out there on the end of the molecule. With one stroke of an enzyme it can turn a small, all-carbon terminal alkyne into a nice, soluble carboxylic acid that’ll probably send the whole structure sluicing right out the kidneys. The liver lives for that stuff, and it drives us medicinal chemists crazy.
If I’m going to be in triple-bond wishing mode, I might as well go all the way: I mean, C-C and C-N are basically the only stable triple bonds that we can use. How fair is that? The other possibilities (with oxygen, sulfur, and so on) are all charged up and reactive, and can hardly even be bottled up or even observed, much less dosed as a drug. (Well, there’s carbon monoxide, the simplest CO case, but although it appears to be a neurotransmitter, most weirdly, it has some problems as a drug candidate). A whole new world of new molecules would open up to us – new shapes, new polarity, stuff that no drug target has ever tried to deal with before – if it weren’t for the laws of physics. Note to self: tell someone else to get cracking on that.
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December 12, 2007
Yesterday’s Wall Street Journal ran a front-page article on the chemistry layoffs that have afflicted us in the drug industry. The piece (by Avery Johnson) focuses on a good example: Bob Sliskovic, the medicinal chemist who first synthesized Lipitor (as in largest-selling-drug-in-the-world Lipitor), and now finds himself laid off by Pfizer:
”Following that initial breakthrough some 20 years ago, Dr. Sliskovic worked on several other research projects, but none panned out. His losing streak mirrors the industry's. A byproduct of the late-19th-century chemical business, pharmaceutical research thrived for more than a century by finding chemical combinations to treat diseases. But after contributing substantially both to human health and drug-industry profits, it has failed to produce significant innovations in recent years.”
That’s a pretty harsh assessment, and I can’t say that I like seeing the past tense of “thrive”. But it’s true that the flow of new drugs has slowed, and now the arguments are all about why that’s happening (and what to do about it). These topics have come up more times than I can count on this site (and will again!), so I won’t go into them in any detail for the moment. But there are plenty of places to lay the blame: Easy drug targets all gone? Too much focus on molecular-level mechanisms and not enough on the end results? Bar now set too high for safety? Management too timid, or too afflicted by short-term thinking? Too much emphasis on blockbusters? Just not enough known about the diseases we’re now trying to treat?
The article makes grim reading for those of us who have been through a layoff or a site closure – I certainly didn’t enjoy mentally revisiting the period a year ago when I (as Sliskovic did) had to phone my wife and tell her that my job was disappearing. And outside of the immediate employment concerns, shutting down a lab is a very sad process:
”In August, Dr. Sliskovic's team stopped doing research and began transferring projects to other Pfizer sites. The labs are now being cleaned, inspected and sealed off. The 177-acre campus is a ghost town of empty rooms and boxed-up equipment.”
Boy, do I know what that looks like. The period before that is even less appealing, when they bring in shredder boxes for people to empty their office filing cabinets into. That’s when you see unusual stuff in the waste bins, such as small piles of plaques and awards that used to be on the desks and walls, since no one feels much like taking any of those home with them. No, I have no desire to relive any of that.
The article raises the question of how many chemists are employed in the drug industry. It’s hard to get a good read on that, but there’s a quote from the Bureau of Labor Statistic that the total number of chemists in the workforce went down from 140,000 to 116,000 over 2003-2006. That doubtless includes a lot of analytical chemists and researchers in other fields than pharmaceuticals, but it’s not a number than can be made to look good. I would think that the ACS would have more specific data, although I know that not all the readers here trust what the organization has to say about chemical employment.
What I can say is that almost all of my colleagues from the Wonder Drug Factory have been able to find jobs. The great majority of the chemists are still doing drug research. Some of them have, though, left the research end of the business, and are working for support companies and vendors. Others have moved over to clinical work or into the medical devices field. A substantial number have, like me, had to move to other parts of the country.
Unfortunately, I don’t see the wave of layoffs ending, although I can’t see them continuing at their current pace, either. There are more large drug companies with problems than there are large companies with secure positions. The WSJ article, for example, has a graph of total head count at Pfizer over the last few years – what’s that one going to look like after Lipitor goes off patent? But offsetting that, to some extent, will be the smaller companies. I continue to think that the pharma research workforce may be shifting away from the largest shops and toward younger companies. Perhaps that’s just because that’s the direction I’ve gone, but then again, I might just be a representative part of a trend. . .
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December 11, 2007
Man, do we ever have a lot of assays in this business. Almost every drug development project has a long list of them, arranged in what we call a screening cascade. You check to make sure that your new molecule hits your protein target, then you try it on one or more living cell lines. There are assays to check its potency against related targets (some of which you may want, most of which you don’t), and assays to measure the properties of the compound itself, like how well it dissolves. Then it’s on to blood levels in animals, and finally to a disease model in some species or another.
Not all these assays are of equal importance, naturally. And not all of them do what they’re supposed to do for you. Some processes are so poorly understood that we’re willing to try all sorts of stuff to get a read on them. I would put the Caco-2 assay firmly in that category.
Caco ("cake-o")-2 cells are a human colon cancer cell line. When you grow them in a monolayer, they still remember to form an “inside” and an “outside” – the two sides of the layer act differently, and they pump compounds across from one side to the other. This sort of active transport is very widespread in living systems, and it’s very important in drug absorption and distribution, and from a practical standpoint we don’t know much about it at all. Membranes like the gut wall or the lining of the brain’s blood vessels do this sort of thing all the time, and pump out things they don’t like. Cancer cells and bacteria do it to compounds they judge to be noxious, which covers a lot of the things we try to use to kill them. Knowing how to avoid this kind of thing would be worth billions of dollars, and would give us a lot more effective drugs.
The Caco-2 cell assay is an attempt to model some of this process in a dish, so you don’t have to find out about it in a mouse (or a human). You put a test amount of your compound on one side of the layer of cells, and see how much of it gets through to the other side – then you try it in reverse, to see how much of that flow was active transport and how much was just passive leak-through diffusion. The ratio between those two amounts is supposed to give you a read on how much of a substrate your compound is for these efflux pumps, particularly a widespread one called P-glycoprotein.
I have seen examples in the literature where this assay appears to have given useful data. Unfortunately, as far as I can remember, I cannot recall ever having participated in such a project. Every time I’ve worked with Caco-2 data, it’s been a spread of numbers that didn’t correlate well with gut absorption, didn’t correlate well with brain levels, and didn’t help to prioritize anything. That may be unfair – after all, I’ve had people tell me that ‘s worked out for them – but I think that even in those cases people had to run quite a few compounds through before they believed that the assay was really telling them something. The published data on these things can turn out to be a small, shiny heap on the summit of a vast pile of compost - the unimpressive or uninterpretable attempts that never show up in any journal, anywhere.
You can think of several reasons for these difficulties, and there are surely more that none of us have thought of yet. These are colon cells, not cells from the small intestine (where the great majority of absorption takes place) or from the blood-brain barrier. They're from a carcinoma line, not a normal population (which is why they're still happily living in dishes). But that means that they’re far removed from their origins, to boot. (It’s well known that many cell lines lose some of their characteristics and abilities as you culture them. They’re not getting the stimuli they were in their native environment, and they shed functions and pathways as they’re no longer being called for). There’s also the problem that they’re human cells, but they’re often used to correlate with data from rodent models. Our major features overlap pretty well (most mouse poisons are human poisons, for example), but the fine details can be difficult to line up.
But people still run the Caco-2 assay. I think that now it’s mostly done in the hope, mostly forlorn, that this time it’ll turn out to model something crucial to this particular drug series. A representative list of compounds that have already been through the pharmacokinetic studies is tried, and the results are graphed against the blood levels. And, for the most part, the plots look like soup thrown against a wall – again. The quest to explain these things continues. . .
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December 10, 2007
OK, let's get the layoff news out of the way for the week. Late last week, Bristol-Myers Squibb announced some long-expected cutbacks. And I know some people in research over there have been rather jumpy, but it looks like this round isn't going to hit the labs. From the sound of it, manufacturing is going to take the brunt of this one.
And that's not good, but it's arguably a better indicator for the company's future than laying off research staff would be. Generally that's one of the last areas to cut for a large company, at least for a large company that plans to discover any drugs. (Which makes you wonder what Johnson & Johnson has been up to, doesn't it?) BMS seems to have decided that its future is in its current strong therapeutic areas, and is narrowing down to make sure that these have enough resources. Good luck to them; I hope it works.
Of course, they're also talking about freeing up some money for partnerships and acquisitions, which is a bit more problematic. Companies this size can do very well bringing in particular drugs that a smaller partner might not have the resources to market, but I hope the company's management isn't picturing some grander strategy. (They don't seem to be planning on getting bought, which is a start). Great Big Visionary Moves in this industry don't have a good history. The time lag of drug development makes them difficult to assess, and difficult to correct when they go wrong. Here's hoping that BMS sticks to what they're good at for now, and that they're correct in identifying just what that is. . .
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December 7, 2007
As pointed out in the comments to this post, the Menger / Christl pyridinium incident made the mainstream German media in the form of an article in Der Spiegel, which is about as mainstream as it gets. Even a news magazine with a page count as high as that one doesn’t cover organic synthesis very often, so I was curious to see how they handled it. Here’s my own translation of the last part of the article, after Christl sends along the bad news that Menger had rediscovered the century-old Zincke reaction:
Menger reacted reasonably, says Christl. “Fifteen minutes after my e-mail he wrote to me that he would immediately review things”. The American at first believed himself to be in the right: that he really had prepared a new 12-membered ring. “I hate to disappoint you”, wrote Christl, equally sure of himself – and referred to a mass-spectroscopic analysis of the products. These had given a higher molecular mass than a 6-membered ring would. But Menger had overlooked an important detail.
“I am no specialist in analytical methods, but I knew the mass spec method that Menger had employed clusters fragments together", says Christl. During the mass spec analysis, a 6-membered ring could appear to be a 12-membered ring. Menger did not know this effect – “A point we did not realize at the time”, he said remorsefully in the journal Nature. Christl reproaches Menger for imprecise work: “He should have asked a specialist in mass spectroscopy”.
Menger must now send in a correction to his work, and Zincke will be acknowledged. That puts Yamaguchi and Menger hard on Zincke’s trail, says Christl with amusement. Both of them used a particular salt, actually called Zincke salt, in their experiments to prepare the supposed 12-membered rings, but they were obviously completely clueless as to the origin of the name.
But another question remains: How could a 102-year-old reaction simply be overlooked, even though every article in a journal is proofread by an external reviewer?
Zincke had naturally published his work at the time in German. At that time, Germany was a center of research, and English was not yet the official language of science.
But was it really just the language barrier that made the entry into Zincke’s work difficult for Yamaguchi and Menger? Christl says: “This literature is so important, that it’s also given in English”. Maybe not Zincke’s complete original article from the “Annalen”, but at least a description of the reaction in the chemical handbooks. These remain in the libraries.
And here lies the problem, that hardly anyone just looks in the books, complains Cristl. “Young researchers just don’t get up any more from their computers. Most of them don’t even know that such a handbook exists”.
Lack of time and overloading of the reviewers are likely to blame. “They have to proofread a publication, bit by bit, every day. How is that supposed to work?” It seems, over and over, that old reactions are unknowingly rediscovered – because scientists simply don’t do their homework, says Christl. “For well-known scientists, the reading of the literature has become a luxury that they can no longer afford”.
I think we missed a golden opportunity in the penultimate paragraph to learn how to say “young whippersnapper” in German. Applying the term to Fred Menger does require a bit of an imaginative leap, admittedly. I’m glad that Spiegel turned down the chance to make this an “if only people knew German” article, though. But even if Christl’s points about literature searching are valid, I’m not sure that this case illustrates them.
I think this reaction would (should) have been picked up by newfangled tools available to those young ‘uns sitting at their desks. Can you get any more newfangled than Wikipedia? You don't even need SciFinder: a Google search for ("primary amine" pyridinium reaction) will give you this, which should be enough to follow up on. But as for hard-core literature searching, a few minutes of reading the pyridinium + amine literature should have turned up this from 1976 or this from 1970. But why go back that far? How about this review in Angewandte Chemie itself from those far-off days of. . .2006?
No, I don't think the problem here is that people don't know how to turn off the computer and go seek out the good ol' dusty handbook. Those have a lot of good information in them, certainly, and no one's ever cranked out better ones than the Germans have. But the problem here is that people didn't apparently didn't spend any time at all checking the literature. And what's more, the folks who send papers to Angewandte Chemie, and especially the ones who review them, don't even seem to be able to find a key reference published last year in the same damn journal.
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December 5, 2007
How many hits can a drug – or a whole class of drugs – take? Avandia (rosiglitazone) has been the subject of much wrangling about cardiovascular risk in its patient population of Type II diabetics. But there have also been scattered reports of increases in fractures among people taking it or Actos (pioglitazone), the other drug with the same mechanism of action.
Now Ron Evans and his co-workers at Salk, who know about as much PPAR-gamma biology as there is to know, have completed a difficult series of experiments that provides some worrying data about what might be going on. Studying PPAR-gamma’s function in mice is tricky, since you can’t just step in and knock it out (that’s embryonic lethal), and its function varies depending on the tissue where it’s expressed. (That latter effect is seen across many other nuclear receptors, which is just one of the things that make their biology so nightmarishly complex).
So tissue-specific knockouts are the way to go, but the bones are an interesting organ. The body is constantly laying down new bone tissue and reabsorbing the old. Evans and his team managed to knock out the system in osteoclasts (the bone-destroying cells), but not osteoblasts (the bone-forming ones). It’s been known for years that PPAR-gamma has effects on the development of the latter cells, which makes sense, because it also affects adipocytes (fat cells), and those two come from the same lineage. But no one’s been able to get a handle on what it does in osteoclasts, until now.
It turns out that without PPAR-gamma, the bones of the mice turned out larger and much more dense than in wild-type mice. (That’s called osteopetrosis, a word that you don’t hear very much compared to its opposite). Examining the tissue confirmed that there seemed to be normal numbers of osteoblasts, but far fewer osteoclasts to reabsorb the bone that was being produced. Does PPAR stimulation do the opposite? Unfortunately, yes – there had already been concern about possible effects on bone formation because of the known effects on osteoblasts, but it turned out that dosing rosiglitazone in mice actually stimulates their osteoclasts. This double mode of action, which was unexpected, speeds up the destruction of bone and at the same time slow down its formation. Not a good combination.
So there’s a real possibility that long-term PPAR-gamma agonist use might lead to osteoporosis in humans. If this is confirmed by studies of human osteoclast activity, that may be it for the glitazones. They seem to have real benefit in the treatment of diabetes, but not with these consequences. Suspicion of cardiovascular trouble, evidence of osteoporosis – diabetic patients have enough problems already.
As I’ve mentioned here before, I think that PPAR biology is a clear example of something that has turned out to be (thus far) too complex for us to deal with. (Want a taste? Try this on for size, and let me assure that this is a painfully oversimplified diagram). We don’t understand enough of the biology to know what to target, how to target it, and what else might happen when we do. And we've just proven that again. I spent several years working in this field, and I have to say, I feel safer watching it from a distance.
+ TrackBacks (0) | Category: Biological News | Diabetes and Obesity | Toxicology
I’ve had reports that some of the animal rights activists are getting loud and lively down in Connecticut, to the point of harassing employees of some of the drug companies there. I remember some of this going on in the early 1990s in New Jersey, but this is the first big outbreak of this stuff I can remember since then. This latest outbreak seems to be part of their long-running (and to my mind misguided) campaign against Huntingtdon Life Sciences.
I won’t go into the specifics of what I’ve been hearing, because I don’t want to encourage the people who do it. What I’ll say is that all this shouting-on-the-street and ominous-flyers-under-the-windshield-wiper stuff doesn’t do the animal folks any credit, not that they care. A rational debate on the issues involved would be just fine by me, and I don’t think it would take very long. But since I doubt that my readership overlaps much with the kind of people who try to publicly intimidate scientists, and I further doubt that those people are open to rational debate. So I don’t see that happening here.
This, then, is just a heads-up for the researchers that do come here, most of whom work, directly or indirectly, with animal assays and the data they produce. Keep your eyes open. It wouldn’t be prudent to bet on all of these activists being harmless. Make sure you know who you’re letting into your building, and so on. The actions of True Believers can be difficult to anticipate, no matter what their cause.
And for my readers outside the industry – yes, we do indeed use animal testing. Mice take the brunt of it, followed by rats. It’s very difficult, expensive, and time-consuming, and we’d drop it in a minute if we could, just for those reasons. But no one knows enough about living organisms yet to do that. Not even close. For the foreseeable future, there’s no other way to do medical research, academic or industrial, basic or applied. Anyone who tells you differently is either misinformed or lying, and anyone who knows better but still tries to shut down the research is ethically deranged.
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December 3, 2007
I was talking about vacuum distillation and recrystallization the other day, and several people pointed out in the comments that large-scale chemistry still relies on these techniques. That’s absolutely right, especially recrystallization. It’s all a question of scale.
These two are bulk techniques – they work out fine on reasonable amounts, but they’re very difficult to run on a microscale with conventional techniques. Distilling a kilo of something is just about as much work as distilling ten grams of it – but distilling ten milligrams, now that’s something I wouldn’t want to be in charge of. Going the other way, distilling ten kilos starts to take you into a another different world, and one of the main reasons operates across the entire scale: surface to volume ratio.
In a distillation from a really large flask, you have to find efficient ways to heat the thing, because just sticking it into a really, really big heating mantle or oil bath gets to be problematic. The surface area of the flask is going up as a square, and that’s what you’re depending on to transfer to heat to the inner volume. But that volume’s going up as a cube. In a 100-mL flask, no part of the contents is more than two or three centimeters from the wall, whereas in a 100-liter system the commute from the edge has grown to something pretty substantial.
Your heating problem is also a mixing problem, since those technologies don’t scale smoothly, either. In a 100-mL flask you can drop a good-sized magnetic stir bar in and whip the solution around smartly with the spinning magnet of a regular stir plate. A proportional stir bar for a 100-liter flask would be a real brick, liable to crash right through the walls of the flask, and you’d need some sort of diesel-powered stirring plate to spin the thing. Needless to say, there are plenty of heating, mixing, jkl and distilling methods for the industrial scale – the existence of gas stations is a testimony to that – but they don’t look much like what people like me use to make twenty milligrams of a test compound.
So much for the big stuff, now take it down to the ten-mg scale. The area-to-volume problem is now reversed. You can’t buy a proportionally sized distillation head, because you’d need a deranged artist of a glassblower to make one. Your tiny volume of solution will just spread out and coat the insides of the smallest distillation rig available. You’re working far within the error and loss of a normal distillation, and your sample will disappear into this gap and never be seen again. I can imagine some sort of microscale rig made out of glass capillaries, although I’ve certainly never seen such a thing. (Surface tension would surely start to become an issue with its operation). Microfluidics is a hot research area, but as far as I know they’ve yet to move on to distillation. I hope someone gives it a shot.
Now consider chromatography. Ten milligrams is plenty of material to work with on an HPLC system. (And if you’re just interested in analysis, and not isolating preparative amounts at the end, ten milligrams becomes a mountainous heap). But running an HPLC on 100 grams is pretty much out of the question. Running even a normal column on that scale isn’t much fun, and when you head up to ten kilos it becomes a major undertaking that you’d do all kinds of things to avoid. (Like, say, spending a week or two trying out recrystallization conditions). The amount of solvent become really substantial, as does the expense and trouble of handling it. It’s not that chromatography doesn’t get done on large scale, it’s just that it gets done only after better alternatives have been completely ruled out.
Recrystallization goes up and down the scale a bit better than these other two techniques. It’s tricky to do on a small scale, but if you have a good solvent combination to form the right kind of crystals you can recrystallize a ten milligram sample if you absolutely have to. One problem with trying to use the technique on that scale is that it generally takes a lot of messing around with the conditions to get a good system, and if you only have ten mgs you probably can’t get away with that. I’d much rather run that sample down an HPLC, though, believe me.
Crystals are much more fun when you’re making a few grams, where you don’t have to worry about every single bit stuck to the sides of the glassware. And the folks working on larger scale just love recrystallization more than anything. It’s true that you have to heat things up at the start, but the heating doesn’t have to be done as critically as in an actual reaction, since you’re generally just trying to get things to dissolve. And once everything has cooled back down and the new crystals have fallen out of solution, it’s just a filtration and wash, and that’s something that can be done well even on a gigantic scale.
+ TrackBacks (0) | Category: Life in the Drug Labs
The lessons of the recent pyridinium follies are old ones. We’re going to have to relearn them again and again – doomed, if like. That’s because as scientists we’re pulled toward two opposite sorts of error when it comes to new ideas, and because in science, everything comes down to new ideas. We’ll have these problems with us always.
The first error, for which the recent retracted papers are the latest posters on top of a thick, stapled, stack, is to become too infatuated by one’s own ideas. It’s a very easy emotion to yield to. To use an unexpectedly R-rated metaphor, it’s the intellectual equivalent of sexual excitement. Under either influence, potentially dangerous decisions and courses of action can begin to seem reasonable and natural, in contrast to how they might appear in less agitated states of mind. Objections, even quite real and forceful ones, are swept aside as being trivial, fit to deal with later after the important business at hand has been concluded.
The problem is, the best scientific ideas induce this state of mind, and in proportion to their scope. I’ve been hit by a few of these, at my own level, and it’s difficult enough. Think about what goes on up in the heights! Can you imagine what it must have been like for James Clerk Maxwell to tie all of electromagnetism up into a perfectly wrapped gift box with three bows on it? Or for Watson and Crick, looking at their DNA model when they were the only two who’d seen it? That intense joy of discovery, of being right, causes people to behave in strange ways. But it’s one of the driving engines of science and always will be.
By the standards of the great discoveries, these latest cases are trivial – as is most work by most scientists, and all of mine, I hasten to add. But the same principles apply. You look at these things and think “Why didn’t they look into known pyridinium chemistry more? Spend some extra time in the library? Some of those salts are surely crystalline – why didn’t they get an X-ray structure as soon as possible?” All perfectly good questions, from outside, and in retrospect. But any of us could end up brushing aside similarly good questions about our own work, and we shouldn’t forget it.
Now for the other error. The excitement of a new idea has a flip side: the depressed (and depressing) feeling that it must have been done before. Surely this can’t be as good as it seems, otherwise it would be known, right? Most new ideas die. Actually, punishingly near all the new ideas in science die, and most of them die quickly. This spectacle horrifies and numbs many scientists, especially if they have sensitive or fearful natures, and causes them to keep their heads down. No breakthrough, no cry.
If you stay in this mindset long enough, the problem takes care of itself: you’ll train yourself to no longer have many new ideas at all, and you need not face the prospect of watching what happens to them. Unusual, potentially interesting things may happen to your experiments, but you won’t be fooled: into the red waste can they’ll go, along with all the other stuff that didn’t give you what you wanted. Nobel prizes have been poured into red waste cans.
Transportation metaphors are safer than copulatory ones. Discovery, then, is a road with ditches on both sides of it, and the hard part is steering between them. Too much optimism and you go whooping off after junk – or worse, catching it and publishing it after writing your name all over it. Too much pessimism, though, and you never accomplish anything at all. I’ve got mud from both sides of the road on my lab coat – how about you?
+ TrackBacks (0) | Category: The Scientific Literature | Who Discovers and Why