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
March 31, 2004
I noticed this post over at A Scientist's Life on some recent instances of retracted papers and scientific fraud. Those two phenomena aren't linked in every case, but they're often seen in each other's company. People do tend to think they're a couple.
The papers were from Science and Cell, two of the really top-shelf journals (links are at the blog above.) I suppose that makes sense, because there's really no point in faking your way into the Transactions of the Ruritanian Academy or something. It would be like counterfeiting nickles. Lou, the biology post-doc blogger, rightly says (with reference to the recent Jan Hendrik Schon case at Bell Labs):
"I've never thought about falsifying data. That goes against my education and belief as a scientist. Naive as it may be, I thought the whole point of science was to look for answers in what is already there - how nature works. I was about to state that it must be biological sciences, but physicists do it too...hey, where are the chemists then?"
Well, clearly, it's because we're too, ahem, upstanding and - haaarrgh - intrinsically honest to do anything of th-aaaackh. . .sorry, couldn't make it all the way to the end of that one. I second that thought about never thinking about faking data, of course, but much as it pains me, I can give some examples of fraud in the chemistry world. To start with, I'll reprise a post from a couple of years ago on my old site, which pointed readers to an article in the journal Synthesis (p. 29, 2002). That paper belongs to the select group of those whose sole purpose is to demolish another one.
The original, now discredited paper was in the same journal over a year before, presenting an interesting reaction that I thought we could make use of in my lab. We actually tried the chemistry out, but it flopped cleanly and completely, giving exactly the wrong product. I chalked it up to the weirdness of our compounds, which was not to be underestimated. Some things worked on them, and some just didn't. We poured the reaction into the red waste can and did something else, which is almost always an option in medicinal chemistry.
But the author of that reference I cite had the same thing happen to him, and he didn't take it as quietly. Going back over the original examples, he showed that the first published work wouldn't, didn't, and couldn't go the way it was reported. Some of the discrepencies could have been put in the "honest mistake" category, subheading "really sloppy honest mistakes," but it seems to me, in the end, that some of it couldn't. The editors of Synthesis seem to have agreed, and to their credit the criticism found its way quickly into print. The (single) author of the non-reproducible work is still listed, though, as a faculty member at the institution he published his paper from - if there have been any consequences of this affair, I haven't heard of them.
I'll dredge up some other examples in future posts. Many of them involve self-deception, at least at first. But as time goes on, the deception becomes contagious, as the originator of the suspect work realizes just how far out from shore he is. "Stepp'd in so far that, should I wade no more, Returning were as tedious as go o'er. . .", as it's put.
| Category: The Dark Side | The Scientific Literature
March 29, 2004
I've had some e-mail from a colleague who says that GlaxoSmithKline is running an ad somewhat similar to the one that I sketched out last week. It ends, he tells me, with the phrase ""Who pays for medicinal research? Pharmaceutical companies do." Sounds like they've taken the results of that opinion survey to heart. Perhaps it'll help. I have to say that I haven't seen the spot (but I don't watch much television, so I might not be a good data point.)
Wonder where and when it's running? Any sightings out there? Perhaps we can assemble a reverse demographic. The ad buys might be rather revealing about where GSK thinks that they can do the most good. Do you target the people whose opinion might be most open to changing, or for those whose opinion would do you the most good if it changed? Generally speaking, those aren't the same groups.
And secondly, my mention of Jazz Pharmaceuticals' ferocious fund-raising round brought a response from someone who actually does venture capital work for a living. And if the whole thing seemed a bit odd to me, well, here's how it seemed to him:
It's ridiculous. The guys who funded that company are going to have their heads handed to them by their limited partners when that deal blows up.
Even IF they successfully in-licensed and developed a couple of drugs, how are they going to make back their money? The guys who bought in got LESS than half the company. You want to see at least 15-20% returns on VC money, or it's not worth the risk. It will have to go public at over $1 billion in the next 3 years to even come close to hitting a decent return for these guys. If they have to wait for 6-8 years (more typical), it'll have to go public over $2 billion. That's what they're betting on. I'd rather buy a lottery ticket.
While I'm on the subject of Jazz, another reader from Big Pharma sent this along:
I agree that it's going to be risky and expensive going this route as a start-up with CNS therapeutics. However, I think you could reasonably argue that this is now more or less the situation (and for all the therapeutic areas) at Bristol-Myers Squibb. All of their recent drugs have been in-licensed, I don't think their Lead Discovery has produced a drug for them in at least 10 years. . .
He's got a point, and BMS has company. There are other companies that have just one or two products of their own to show for that same stretch of time. I'll name Pfizer and Schering-Plough just for starters. The problem with running an inlicensing operation these days is that there are too many people trying to play the same game. Pipelines are so thin that any outfit with a real candidate can hold out for an insanely good offer (remember the crazy sums that BMS laid out for things like Erbitux?) So where is Jazz going to find these great drug candidates? And how much are they going to have to pay?
| Category: Business and Markets | Why Everyone Loves Us
March 28, 2004
Synthetic organic chemists rely a lot on inorganic chemistry. We let metals do a lot of work for us, particularly when it's time to do the real arc-welding of carbon-carbon bond formation. I have a pretty typical synthetic background, and over the years I've used palladium, platinum, sodium, iron, copper, rhodium, aluminum, mercury, silver, manganese, lithium, titanium, chromium, cobalt, zinc, ruthenium, vanadium, tin, magnesium, cerium, potassium, and probably a few more that escape me right now. Never sit near a chemist and give him any excuse to rattle off a list of elements.
I've never used elemental nickle metal, but I have broken out some of its salts from time to time. I especially enjoy the vivid green of nickel chloride, whose solutions look for all the world like lime jello. Not that you'd want to substitute that in your favorite recipe: nickle salts are rather toxic, and are suspected carcinogens to boot. But I'd work with them all day long to avoid dealing with another nickel compound, its tetracarbonyl.
That's a complex of nickel with carbon monoxide. CO has a good amount of electron density left on its carbon, and it'll line up on a metal atom, slotting into its electron orbitals and making itself at home. You can find carbonyl complexes of all the transition metals, as far as I know. Many of them are liquids, which is rather disconcerting when you consider their metal heritage.
Nickel carbonyl is a liquid, but it can barely restrain itself from being a gas. It boils at 43 C, so it has a pretty substantial vapor pressure, and that's a real problem. Said vapor, as you'd imagine, is rather weighty. It's not one of your wafting-away-on-the-summer-zephyr sort of vapors; it's more like a sort of ghostly molasses. It's so heavy that you really can't rely on a standard laboratory fume hood to contain it, because that's not the sort of hazard they're built for. Depending on the air flow and the sash, the stuff can just ooze right out the front of the hood and pour out into the lab.
You don't want it there. Breathing it is most unwise, because those CO ligands are not stapled on very well. If they find another metal that appreciates them more, they'll bail out, and an excellent candidate is the iron in your hemoglobin. There go four equivalents of carbon monoxide into your blood cells, and there's only so long you can keep that up. And there's the nickle, too - alone, bereft, with only your proteins to complex to. Wonderful. Recall that the metal is toxic all on its own, and you've now dosed in the most bioavailable manner possible. If you make it through the carbon monoxide spike, you have long-term metal poisoning to deal with.
Even if the vapor doesn't get the chance to wander around poisoning you, it can amuse itself right in your fume hood. If it rolls across a hot surface, of which there are no shortage in most working hoods, then it can explode, leaving behind a vile haze of carcinogenic nickle soot. An exploding toxin with a high vapor pressure - I just don't know what else you could ask for in a laboratory reagent. No doubt it does many interesting and useful reactions. They can save 'em for me, because I'm not that desperate yet.
| Category: Things I Won't Work With
March 25, 2004
No time for a real update today, but (thanks to Instapundit) I wanted to recognize Nobel winner Norman Borlaug, whose birthday is today. He should be much better known than he is, since (as the man behind the "Green Revolution") he has beyond a doubt kept hundreds of millions of people from starving to death.
What's remarkable is that he's still out there, doing what he's been doing for the last forty years. Not everyone is happy about it, though, as this Gregg Easterbrook article in the Atlantic Monthly and this Ron Bailey interview from Reason show. More information can be found here, at the site of the Borlaug Heritage Foundation.
A worthy goal for a person would be to attempt to accomplish one-tenth as much.
| Category: General Scientific News
A couple of items from the business and economic side of things: First off, Daniel Gross over at Slate's Moneybox column has an excellent take on the stupidity of the French government's meddling in the Aventis takeover. Novartis has been producing bid-making noises, but says that the French government has to get out of the picture for it to consider getting involved. Says Gross:
"What the French and German governments are really doing here is erecting artificial obstacles to a deal. These barriers to foreign bidders drain the pool of potential buyers and hence suppress asset prices-ultimately making the target firms weaker and poorer."
Exactly right. The same kind of argument can be made against all sorts of other protectionist schemes. And no, reimporting pharmaceuticals at an artificially low fixed price does not count as free trade in my book. Free trade is when everyone markets their goods wherever they want to, charging whatever price they believe that the market will bear. We should give it a try sometime, and that goes for drugs, for wheat, for shoes and sugar and silk. The lot. That it should apply to the buying and selling of companies should be obvious, but not, it seems, in Europe.
The other thing that caught my attention was a headline in the New York Times. "Drug Company with No Products Raises 250 Million." Sounds good to me! Many of us work at companies with almost no products - does that count? Can we get, say, two hundred million on the same principle?
The company in question is Jazz Pharmaceuticals, founded by some ex-Alza folks. Mighty strange name for a drug company, guys. They're going to develop CNS drugs, but they're not going to discover any of them. All of them will be in-licensed. Now, this business plan is not insane on the face of it. The idea of a "virtual drug company" has been floating around for some years, and occasionally it comes in for a landing. Such an outfit would be, essentially, a regulatory and marketing services company, for research organizations unwilling or unable to do those tasks themselves.
But neuropsychiatric drugs are notoriously tricky. Their developmental paths are long, expensive, and have many exciting plot twists. If I were going to be an in-licensing firm, I don't think this is the street I'd choose to hang out my shingle. But hey, I drive a car that I bought before the Berlin Wall came down. These Bebop folks are the ones who just set a record for second-round financing. Good luck to 'em.
| Category: Business and Markets
March 23, 2004
Here comes a fine snapshot of the shape that my industry is in with the public. The Sunday-supplement magazine Parade did a cover story last weekend on medical research, and they commissioned a survey to go along with it. Here's the PDF of the results, obtained in a collaboration with ResearchAmerica, an academic/industrial advocacy group.
One question that particularly caught my eye was "Who do you think pays for most of the medical research done in this country?" 59% answered that the government does (and thus the taxpayers), and 9% said that the pharmaceutical companies do. The Parade article correctly pointed out, though, that industry actually does over half of the research by itself. Looking at that response, I can't help but see the footprint of the idea that I was dealing with here a couple of weeks ago, that NIH does all the drug discovery and we drug companies just swoop down, flap away with the swag in our talons, and feast on the profits.
Another answer that I found grimly enjoyable was to the question "How long do you think it takes, on average, to bring a new drug to market?" 29% of the sample answered 1 to 4 years, and 40% answered 5 to 9. Would that it were so! The record in my experience is just short of 11 years from discovery to regulatory approval. I know it's occasionally done faster, in special cases, but it sure runs slower a lot of the time, too. Makes me wish that they'd asked people to ballpark how much it costs, too. . .
I should note that the responses, overall, were very favorable toward medical research. People want more money spent on it, they support tax and regulatory reforms which would make it easier to perform, and so on. They just have no idea of who does it, or how long it takes.
So, what would it take to get the word out? I can just about sketch out a commercial in my head, just sitting here at home. No smiling senior citizens, no dogs, no athletes or running children. Just something like this:
CLOSEUP of some solution stirring in a round-bottom flask: "John Doe had an idea in his lab for a new medicine. . ."
MONTAGE of white-coated researchers pouring, pipetting, wheeling carts, etc.: ". . .and for once, this one seemed to work. His company got interested, and they made more of it. . .
PAN past a pilot-plant reactor sluicing out product: ". . .a lot more. His compound was tested over and over. Tested for how well it could treat its disease, tested for safety a dozen different ways to see if it could really be a drug. . ."
DISSOLVE to a physician dispensing a service formulation to a volunteer: ". . .and for the first time in John's career, something he invented made it all the way into patients."
TIME-LAPSE DISSOLVES of roomfuls of people fading in and out: "Then the real work started. Small groups of people, then hundreds, then thousands tried his compound in different ways, at different doses. It took years, and it took hundreds of millions of dollars. . ."
CLOSEUP of a pill rattling out of a container in slow-motion: ". . .to find out - that this wasn't going to be the one. Not quite."
DISSOLVE to head shot of researcher slowly flashing wry, determined smile: ". . .but John was still in his lab. Still working. And one day he had an idea. . ."
SUPERIMPOSE a closeup of another solution stirring in a flask, and fade to lettering: America's Pharmaceutical Companies: Where the Drugs Come From. "America's Pharmaceutical Companies. We'll never stop. We promise."
OK, I'm a professional chemist, not a professional PR man. But tell me, would an ad like that really do a worse job of informing people than the stuff we're already doing?
| Category: Drug Prices | Why Everyone Loves Us
March 22, 2004
There's an interesting piece over at 2 Blowhards (a culture-blog I'm going to have to permalink soon) on business versus craft. Their example is from a Los Angeles Times article on animators. Many Californians in that trade have had their jobs fall victim to new technology (and new lower-wage sources of labor.) You'll think that you know where this is going, but just watch:
It's impossible not to feel for these people, since it is clear that collapse of Disney animation, at least, was hardly the fault of its lower-ranking employees. The Eddie Gorals of the animation world didn't screw up. No, clearly, the 'suits' are to blame here for bad business and artistic decisions (like the last four or five Disney animated movies, with the notable exception of "Lilo and Stitch.")
And yet, is it really fair to blame the 'suits'? Is it really the responsibility of the 'suits' to ensure that the Eddie Gorals of this world are employed at reasonably well-paid salaries doing what they love? Isn't part of the problem that the Eddie Gorals of this world want to beaver away at their craft, and don't want to be bothered to think about raising money and launching new projects that would ensure that they stay employed?
I know the tradeoff Eddie thought he was making-the 'suits' would get the big bucks and he would settle for a middle-class life-style coupled with a steady-stream of craftsmanly job satisfaction. But that didn't take into account the more-or-less inevitable outcome: that the suits (to whom Eddie had effectively outsourced the 'business' issues he preferred not to focus on) would screw up! It took them awhile, but they managed it. And he (not they) paid the price.
Blogger "Friedrich von Blowhard" makes a good point, and it's one that you don't hear made very often. It goes for the drug industry, too, as many of my readers there will have sensed immediately on reading the above. Employees at the smaller companies know this principle well, because so many of those companies collapse. Everyone working at a biotech has one eye on the exit, ready to bolt if things start to go bad.
But it works like that in the big companies, too, or it should. If you think that your high-flying pharma company is executing one of those slow, stately turns that will take it directly into the side of a mountain, you should start getting ready to jump. It can be hard, because there are often personal and family reasons to stay where you are. There's not always another place to go, either, and I appreciate that problem (having been there myself.)
It can also be tough to leave behind the vested bonuses, profit-sharing plans, and so on that your tenure entitles you to. You feel as if you can't afford to go anywher else. But those things are going to disappear if the company really does grind into the gravel, and that's when you can least stand to have it happen. I've seen some distressing examples among people who kept buying lots of their company stock in their retirement plans, for example, because it did so well. And because it did so well, it came to be a big fraction of their portfolio, well above the limits that they'll usually let you set for new purchases. And when said company began throwing piston rods and leaking oil, the stock tanked, taking all those retirement plans down with it. Then the bonuses stopped, and then the firings started.
No, Friedrich is right. You have to keep a clear eye on the people running your company. If you just read the company's official statements, and just listen to the stuff at the "State of the Firm" meetings, you'll think that everything is fine, even if it isn't.You need to think for yourself, and get all the external advice you can (from the investment community, the trade press, and so on.) Capitalism is work - that's one of the reason why it works.
| Category: Business and Markets | Life in the Drug Labs
March 21, 2004
Mentioning well-heeled research establishments that don't produce results brings up an interesting question: is there a negative correlation between funding and productivity?
You might think so, given the example cited in the previous post, and given the cases cited in Robert S. Root-Bernstein's Discovering. There have been many great scientific feats performed with what seemed like substandard equipment for the time. But does that imply causality, or does it mean that a first-rate scientist is capable of great work even under poor conditions? (A special case, perhaps, is Alexander Fleming. One time in his later years, he was being given a tour of a more up-to-date research site, and someone exclaimed "Just think of what you might have discovered here!" Fleming looked around at the gleaming work surfaces and said "Well, not penicillin, anyway.")
I'm not arguing for poverty. I think that a certain minimum level of funding is necessary for good science - below that and you spend too much time in grunt work, the equivalent of digging ditches with kitchen spoons and mowing the lawn with scissors. But once past that, I don't think the correlation of budget and results is all that good. There's perhaps a broad trend, but nothing you'd want to stake your career on.
That said, note that there are many ways to spend huge amounts of research money. You can lavish all sorts of new facilities and state-of-the-art equipment on people, or you can spend equal amounts by running a larger effort and trying to run many more projects at the same time. The people in the first case will live in a rich environment, while those in the second can feel rather deprived. Overall budgets aren't necessarily a good indicator.
I'd argue that you want people to feel reasonably comfortable, but not luxurious. If you have to scramble a bit for resources, you end up being more, well, resourceful. I'm not talking about redistilling your wash acetone (that comes under the spoon and scissors heading.) But if you have an idea which would require, say, a completely new hundred-thousand-dollar piece of equipment, you might be able to think your way out of that if it would be hard to get. While, on the other hand, if you just have to wave your hand and the stuff appears, you might get in the habit of not thinking things through.
| Category: Who Discovers and Why
March 18, 2004
A reader's e-mail got me thinking about this topic. It's worth a number of posts, as you'd guess, since there are many substantial differences. Some are merely of degree (funding!), while others are of kind.
But the funding makes for larger changes than you'd think, so I'll get that one out of the way first. When I was in graduate school, my advisor's research group was actually pretty well-heeled. We had substantial grant money, and none of us had to be teaching assistants past our first year. But even so, we had to watch the expenditures. For example, we didn't order dry solvents, in their individual syringable bottles, from the chemical companies because those were too expensive. Instead, we had our solvent stills, which (to be fair) produced extremely good quality reagents at the price of the occasional fire.
Grad student labor is so cheap it's nearly free, so making expensive reagents was more cost-effective than buying them. (At least, it was if you weren't the person making them.) I had a starting material that's produced from pyrolysis of corn starch (levoglucosan, it's called, and I'd be happy to hear from anyone who's worked with the stuff.) At the time, it sold for $27 per 100 milligrams, and since I used it in fifty-gram batches, that was out of our price range for sure.
So I pyrolyzed away, producing tarry sludge that had to be laboriously cleaned up over about a week to give something that would crystallize. (I saved the first small batch that did that for me back in the summer of 1984, and it's sitting in the same vial right next to me as I write. The label looks rather distressingly yellowed around the edges, I have to say.) A kilo of corn starch would net you about fifty grams of starting material, if everything worked perfectly. And if it didn't, well, I just started burning up another batch, because it's not like I had anything to do that Sunday night, anyway.
When I got my first industrial job, it took me a while to get all this out of my system. I needed an expensive iron complex at one point, about six months into my work, and sat down to order the things I needed to make it. My boss came by and asked what I was up to, and when I told him, asked me how much the reagent itself would cost. "About 900 dollars", I told him, whereupon he told me to forget it and just order the darn stuff. He pointed out that the company would spend a good part of that price just on my salary in the time it would take me to make it, and he was right, even at 1989 rates.
So we throw the money around, by most academic standards. But there can be too much of a good thing. There's a famous research institute in Europe, which I'm not quite going to name, that was famously well-funded for many years. They had a very large, very steady stream of income, and it bought the finest facilities anyone could want. Year after year, only the best. And what was discovered there, in the palatial labs? Well, now and then something would emerge. But nothing particularly startling, frankly - and from some of the labs, nothing much at all. You'd have to have a generous and forgiving spirit to think that the results justified the expenditure. There are other examples, over which for now I will draw the veil of discretion.
| Category: Academia (vs. Industry) | Graduate School
March 17, 2004
I sent off a manuscript to a chemical journal not long ago. There's an initial flurry of e-mail activity when you do that - we've received your manuscript, we've sent your manuscript out to reviewers - and then a more or less prolonged period of silence. The next thing you hear is whether the paper's been accepted or not, along with the referee comments.
Mine were the usual mix of helpful suggestions and things that make you roll your eyes. One of the latter was a comment that immediately pegged the reviewer as someone from academia. They noticed that the data from our primary assay, against a human enzyme, didn't always match up well with the secondary assay, which was against a rodent cell line, and wanted some more explanation for why some groups of compounds weren't active.
To which I could only reply "You and me both!" That's a constant problem in medicinal chemistry. A majority of projects are set up in that format, with a cell-free assay as the first filter, then cells expressing the target as the next hurdle. And it's just about inevitable that there will be whole groups of compounds that work fine in the first assay, but just wipe out in the second one.
Why should that be? As far as we know, there are two general ways that compounds can get into cells: passive transport and active transport. The passive route is just diffusion across the cell membrane: "Wonder drug? You're soaking in it!" It's affected by broad trends in molecular size, polarity, and so on. The second route is when your compound hitches a ride on some transport protein.
There are hundreds of these things involved in opening up channels into and out of the cell. Some of the famous ones move ions (calcium, potassium and the like), which makes sense. Those are small and electrically charged, so they're not going to just wander across the membrane on their own, and the cellular machinery depends on keeping such membrane potentials tightly controlled. Then there are transporters for large proteins, which are too huge to diffuse by themselves, and for essential classes of small molecules like fatty acids.
No one's sure how many of these things exist. Just in the last few years, there's been a whole new class discovered, the aquaporins, which (as the name implies) move water itself across the cell membrane. You wouldn't think that you'd need an active transport system for that (at least a lot of people didn't think so) but the things turn out to be ubiquitous. If there's a transporter for water, there can be one for anything.
The efflux pumps I spoke of the other day in antibiotic resistance are active transport proteins, too, naturally. Those complicate things by taking compounds that diffuse perfectly nicely into cells and making them look like they're bouncing off a layer of armor plate instead. You'll also get that effect when your standard project compounds ride in on some transport system, then you make some small structural change which causes your drug to lose its train ticket.
It's a lot of work to figure out what's going on, and often you can't get a handle on it, anyway. Many of these transport systems don't have specific inhibitors, so it's not like you can switch them off one by one to see which one is the problem. If you have a good way to monitor your compound on a cellular level (like a fluorescent probe), you can actually see the things going in and being pumped back out sometimes, or you can see if the transport system can be saturated as you load up on drug. But there's no way you can do this for hundreds of drug candidates on every project.
So, it's just one of those things. I'm on a project right now that has the same thing going on. We make tiny changes to our molecules, and the cell activity suddenly gets a hundred times better, or a thousand times worse. But are these trends going to translate to the cells inside a real animal? And if they do, will they be relevant to the active transport systems in humans? Bite your tongue.
| Category: Drug Assays | The Scientific Literature
March 15, 2004
In my March 11 piece below, I mentioned the possibility of Pravachol competing on price with Lipitor. But over at Forbes, Matthew Herper has pointed out that it's currently more expensive. What BMS is going to do with this drug, I can't imagine.
There's also a good story in the Newark Star-Ledger about the whole comparative-trial situation. (That paper does a pretty good job with the drug industry, since so many of the big players are right in its back yard.)
| Category: Business and Markets | Cardiovascular Disease | Clinical Trials
Want to feel old? Then let it hit you that there are entire scientific journals you used to read that don't exist any more. I was looking up an old paper the other day in a German chemical journal, when it struck me that there aren't as many of those as there used to be. The grand old Chemische Berichte, for example, ceased to exist a few years ago (along with a whole group of other publications) and was subsumed in the rather blandly titled Chemistry: A European Journal. Even the journals that (theoretically) publish papers in German don't have as many, like Synthesis or Helvetica Chimica Acta. When's the last time anyone saw a German-language paper in Tetrahedron Letters? Do they even accept them any more?
They used to publish them, years back, and French as well. The French chemistry literature is in even worse shape than the German, because it didn't start from such a position of strength. I used to pull the occasional paper out of Comptes Rendus in a literature search, but that journal spent decades sinking slowly into obscurity. Another outlet for French was one of my old favorites, the Benelux journal with the flowery name of Recueil de Traveaux Chimie du Pays-Bas. The older generation can remember when it formed from the separate Belgian and Dutch society journals (surely there wasn't a Luxembourg one?), but not me. It, too, disappeared into the aforementioned Chemistry.
No, for a long time now publishing chemical work in anything other than English has been the sign of second-rate material. That goes for Japanese and Chinese chemistry, too. There are a number of "internal" journals in each country, but the good stuff appears in English. My literature searches in SciFinder or Beilstein still turn up journals I've hardly heard of, but the papers are almost always in English, or an approximation thereof.
And at this point, it takes a lot to come up with one that I've hardly heard of, I can tell you. Journal of the Siberian Oil Chemist's Association? I've seen that one, along with most of the others from the old parallel-universe world of Soviet science publishing. The Royal Thai Chemical Society's journal? Check. That old weekly Swiss medical bulletin? Yep. The trickiest one I've had in recent years was the house research organ of a New Zealand medical school, but an interlibrary search turned it up.
Mind you, there are a few journals we still have with us that could stand to disappear. I hate to say it, but when was the last time anyone paid any attention to anything in Accounts of Chemical Research? Why is it that I can count on one hand the number of papers I've ever needed from Biochemistry? The continued existence of Synthetic Communications has long been a mystery to me as well. Perhaps some of these will provide nostagia for the next generation.
| Category: The Scientific Literature
March 14, 2004
Some miscellaneous updates tonight, in addition to the note appended to the post below. It seems that Sunday nights don't often leave with time for more extensive blogging, and the world events of the last few days have made their claim on my attention as well. This isn't going to be one of those dull years, not that I expected it to be. In fact, I'm not sure when we're going to have one of those again.
Some readers (rather few) may be wondering what's been up with my long-running series of odd experiments, last seen crashing to earth in a rain of feathers and melting wax. I haven't set anything up in the lab since that, but I've been busy working on a presentation to go public (inside my company, anyway) with my ideas. The project, if it's going to work at all, is too big for me to do in the scientific equivalent of my garage. I'm going to make my case for some formal support, and it'll be interesting to see how that's received.
On another front, I wanted to mention that I closed out my short position in Imclone at about $45/share, a nice round loss from the $40 where I went short. I'm keeping an eye on the stock, and if it continues to rise (up into, say, the 60s with no change in the underlying situation), then I'll consider shorting it again. For now, though, discretion was the better part of a capital-gains loss. I continue to think that many IMCL investors suffer from an excess of optimism, but that's one of the engines of the market, isn't it? (I did make up that loss and more by shorting MSO, Martha Stewart's company, though. Write and I'll bore you with the details.)
And the Sanofi/Aventis dance continues, with Novartis hovering over the whole proceedings. This is yet another situation where those who say, don't know - because those who know aren't saying. Most of the public statements are designed to be, well, merely public statements, so their information value is questionable. It's going to be a while before we know how this one comes out, so I haven't been (and won't be) covering every twist and turn. If anything dramatic happens, I'll weigh in.
| Category: Birth of an Idea | Business and Markets
March 11, 2004
Just a brief note today about the "PROVE-IT" study that Bristol-Meyers Squibb ran and has now reported on. This was their big shot at Pfizer's Lipitor, their chance to show that their own statin, Pravachor, was just as good or better. The study was big, it was long, and man, was it expensive. It's just the sort of thing that I was talking about when I wrote recently about comparative drug trials.
And it shows why more of them aren't done. Because, as is well known, when you strike at a king, you have to kill him. BMS found, no doubt to their dismay, that Lipitor is actually a better drug. It's not a gigantic difference, and you can still argue about the dosages, but BMS's drug definitely failed to realize the hopes they had for it. Here are two competing views on the issue, one from DB's Medical Rants (keep scrolling up) and one from Medpundit.
Now what? How do they promote it? The question that BMS is going to get is "Why should anyone take your drug instead of Lipitor?" The only thing I can think of is for them to compete on price. "Take Pravachor - it's proven to be sort of, you know, inferior, but it's sure cheaper!" Doesn't quite have that compelling zing, does it?
If comparative drug trials are going to be done, they're either going to have to be required by law - in which case, as I pointed out, we in the industry will pass along those costs to the consumer, thanks - or they'll have to be done by a third party. (In which case it'll be paid for by everyone who pays taxes, not just the eventual users of the drugs involved.) If you're waiting for more companies to do them on their own, you're going to have a long wait. Especially after something like this happens.
I'll leave everyone with a homework question: Can anyone think of another case - I can't - where a company sponsored a study of their product against a competitor, found that theirs fell short, and publicized it? UPDATE: I mean, outside the drug industry. It's happened several times to us (Zyprexa!) I'm talking Ford / Honda, Dell / Gateway examples, and I can' think of one. Admittedly, as I've said before, health care is different, but still. . .
| Category: Business and Markets | Cardiovascular Disease | Clinical Trials
March 10, 2004
There's some fresh news in the (quite possibly endless) debate about the vaccine preservative thimerosal. The Institute of Medicine is working on another report, due in several months. Their last report, in 2001, found no evidence to support a link, but didn't dismiss the possibility, either.
I've written about this topic before. My belief, then and now, is that autism and thimerosal are very unlikely to be related. I haven't seen any data that make me lean the other way, and the evidence against a link has continued to pile up. One of my objections to the hypothesis has been that it's hard to rationalize, mechanistically. Mercury compounds are certainly neurological bad news, but autism hasn't generally been noted as a symptom of developmental mercury exposure. (There's a different set of effects, instead.) It's hard to come up with an explanation for why thimerosal's effects would be different and specific, while still partaking of the general toxicity of mercury compounds. (Why no rising epidemic of, say, cerebral palsy?) And there's the matter of the low dose, too.
But now there's a paper in Molecular Psychiatry by a team of researchers (from Northeastern and several other schools) which suggests a mechanism. They're looking at the synthase enzyme that produces the amino acid methionine, which is an important source of methyl groups for other enzymatic systems. DNA methylation is particularly important in gene expression, and many cellular growth factor pathways seem to have a methylation requirement in them as well. They've found that thimerosal is a powerful inhibitor of two particular growth-factor driven methylation reactions, with an IC50 of about 1 nanomolar.
Single-digit nanomolar is the kind of inhibitory constant that we look for in a new drug, too, so it's certainly plausible that that could have effects in vivo (if the pharmacokinetic behavior - blood and tissue levels of the compound - go along.) The paper points out that the ethylmercury blood levels produced by thimerosal-containing vaccines are in the 4 to 30 nM range, which is enough of a multiple of the IC50 to keep the hypothesis going (but see below.) So is this the proof against thimerosal, or not?
Well, on one level, this could answer some of my mechanistic objections. But I still have the same questions as before. This could be a refinement, but not enough by itself to establish a link. We're still in the same place: It's not that I can't imagine that thimerosal could be toxic, it's that I have trouble with it being toxic in just such a way as to produce only autism. Methylation pathways are ubiquitous - how does such a specific phenotype show up from this? (More such scepticism from an immunologist at McGill is here.
The authors do suggest some possible answers. Perhaps some individuals have a less robust methylation system than others, especially in specific brain development pathways, and are thus predisposed to thimerosal-induced damage. That's definitely a hypothesis worth investigating. If that looks like it's the case, I'll have to upgrade my take on the whole idea, subject to the 800-pound-gorilla in the last paragraph below.
And they suggest some limitations to their work. For one thing, they're working on cultured cell lines, which are tumor-derived and may well respond quite differently than primary cells in vivo. They also point out the potential complication that their cells have not fully differentiated into neurons. It's responsible of them to mention these factors.
I also wonder what the hit rate is in this assay - if we run a few thousand natural products or other environmental-exposure compounds through, how many are positive at nanomolar levels? I could also add that the ethylmercury blood levels they quote might not mirror the levels in the brain. That's been a battleground in the whole thimerosal debate, because we don't have definitive mercury pharmacokinetics in the brains of human children (and I sure can't think of an acceptable way to get 'em, either. The methods we use for that kind of data in rodent studies are clearly not going to apply!)
But my biggest objection to a thimerosal/autism link is epidemiological. So far, there seems to have been no change in the autism rate in response to the discontinuation of thimerosal. Data continue to be collected, of course, but there's no apparent connection, even from countries that eliminated the compound before the US did (and thus have a longer baseline.) The real-world numbers trump any amount of biochemical speculation. That goes for my own ideas as well, as my research projects demonstate to me regularly.
| Category: Autism | Toxicology
March 9, 2004
I've been remiss in not mentioning the new paper that's coming out in Physical Review E from the group that's reported possible sonochemical fusion. Their original paper from two years ago was the subject of one of my early blog posts (see the March 4 entry.) I'm very happy to hear that this work is still going on, and has been further refined. This increases the odds that there's something here worth studying. Physical Review is not a pushover of a journal (and neither is Science, where the first paper appeared), so the Purdue/Rensselaer effort has already made it through tougher scrutiny than other unconventional fusion claims. (I know that they've had trouble getting their papers through, but that's to be expected.) This groups seems to be doing this the right way, responding to critics by quietly improving their work and not rushing out to claim Instant Free Energy, Persecution by the Powers That Be, and all the rest of it.
I've mentioned before that the Pons-Fleischmann debacle of 1989 is a very fresh memory with me. I've tried several times, unsuccessfully I think, to write about it in blog posts and other places. I'll give it one more try, with apologies to those who've heard me speak about it before.
It's hard for me to convey what a bolt from the blue that news was. I was living in Germany, doing my post-doctoral work. That Easter Sunday I heard the news on Armed Forces Radio, which I had playing in my lab. (Yes, I was in the lab.) I'd like to be able to see my reaction - I'm sure my head jerked up abruptly to stare disbelieving at the radio. The report credited the Financial Times newspaper, so I trotted down to my car and drove to the train station to buy a copy. I still have it, the original color of the newsprint somewhat altered by time and oxygen.
The weather was nice that day; winter was finally breaking apart in Germany. I headed back to my lab for a while, reading the paper as the sun came in through the windows, before going off to an Easter meal with my labmate and his family. I remember his father asking him in German, using a slang term equivalent to "Yanks": "Have you heard? The Amis have done nuclear fusion!" He was smiling. And I was proud, I was excited, and I didn't know anything more than I'd read in the newspaper. All I could say was that something huge might have happened.
It hadn't. That whole castle began to crumble back into an entropic sandpile as the tide came in over it. It took months, it took years, but it's pretty safe to say that dream is as good as dead, despite occasional odd reports. (Or because that's all there are.) But for a while there, I knew what Wordsworth was talking about when he wrote "Bliss it was in that dawn to be alive", although in a better cause, I hope. I was absolutely elated by the news, by what it could mean - cheap energy, a transformed world, oh, the usual. But just as much, what excited me was the thought that discoveries like this were still out there to be made. The world was strange and it had surprises up its sleeve.
I'd waited to hear more about the sonochemical fusion work ever since it came out, but after a few weeks everything was quiet. No arguing, no counterclaims - I'd already had sinking feelings of regret that another attempt at a breakthrough wasn't working out. So it was another surprise when I saw the news. Winter's beginning to break here - I'd been able to enjoy the temperature when I went out to get the paper from the yard. And here it was, the headline about "fusion results replicated."
The hair stood up on my arms and on my neck. But this time, instead of pacing around alone in my lab, I tried, in the kitchen of our house, to explain to my two small children why I'd jumped up like that. I've been somewhat altered by time and oxygen, but I'm glad that such things might still happen, and that I can still react like this when they do.
| Category: General Scientific News
March 7, 2004
I see that Steven den Beste linked to me as a general source of med-chem info, which was good of him. He was discussing resistance in treatment of tuberculosis (on the way to a broader point about current events), so I thought I'd say a few words about antiinfective drugs.
As I've mentioned in the past, it's not an easy area. At least, not any more. This was one of the first frontiers for medicinal chemistry (think Salversan for syphilis, sulfa drugs, penecillin and so on.) But it's clear that no one realized the long-term consequences of the free use of those early drugs. And even if they had, I doubt if much would have changed. There wasn't much incentive for restraint, not when people who were marked for death suddenly getting up and walking around.
It's easy to forget how serious infectious disease was back then. People are horrified now when there's a death like, say, Jim Henson's: a rampaging septic reaction that kills within a few days. But go back a hundred years, and that sort of thing happened all the time. Earaches could kill you, things that we'd consider bad colds might end up killing you. A toothache could signal that the end of your life was a week or two away. No, once drugs came around that could fight this sort of thing, no one felt like holding back.
But now we've burned out a lot of the easy targets. There are, broadly, two classes of drug targets against bacteria and other infectious agents. The first are enzymes and pathways unique to the pathogen, and those are naturally the best. Penecillin and all the related drugs fall into this category. They mess up the synthesis of the bacterial cell wall, leaving the affected organisms naked to the world and thus easy prey for the immune response. Cells of higher organisms don't make such walls, so you can beat on that pathway all day long without much risk.
The second group are targets that are present in humans as well, but with enough variation in the protein that you can hope for a selective compound. This takes more work, most of the time, and sometimes you can't separate the activity enough to be useful. Many bacterial enzymes are distant cousins of their human equivalents, but many others are too close to work against.
And with either class of drug, you have resistance. That's what they didn't appreciate in the early decades - and if they did, they underestimated it. Bacteria have such short life cycles, and there are so many of them. They're an ideal laboratory for evolution, and when humans came in and put the selection pedal down, the changes started and haven't stopped.
One common mechanism is for the target protein to end up mutating. There's a good amount of genetic variation in the bacterial population, and some of the group you're trying to hit might have a form of the protein that doesn't bind your drug. Given enough bacteria or enough time, there are bound to be some. So you treat with the drug, everyone else dies, these naturally resistant organisms have the whole field to themselves, and they run wild.
Sometimes the bacteria whip out another protein to take care of your drug all by itself. That's what happened to penicillin. Some bacteria turned out to have an enzyme to defend against such compounds (which are, after all, found in nature as antibiotics.) The enzyme, beta-lactamase, cleaves the crucial four-membered ring at the heart of the whole drug class. Naturally enough, this enzyme is all over the place now. (Thus the drug Augmentin, which contains a penicillin derivative and another drug, clavulinic acid, which inactivates beta-lactamase. But as you could guess, organisms have appeared whose beta-lactamase isn't affected by it.)
Yet another resistance mechanism is an active-transport pump. These are membrane-spanning proteins that physically expel the drug molecule once it enters the bacterium, pumping it right back out before it can do its job. (Cancer cells do the same thing, by the way.) What makes all of these such a problem is the habit many bacteria have of swapping DNA segments like trading cards. It's hard to measure, but I'm sure that over the years we've selected for accelerated DNA transfer. Under stress, the active traders have an edge, since they have a better chance of swapping in some DNA to code for the necessary inactivating enzyme or pump.
It's a battle. And from all appearances, it's never going to end. We're fighting tenacious, adaptable organisms that pull out all the stops all the time. They don't sit around fretting about the younger generation and their DNA-swapping ways, or worry that they're losing their essential staphylococcusness by taking on all these new characteristics. There are no spirochetes grousing that an arginine at that position was good enough for their granddads, and it's good enough for them. No, they'll do whatever it takes. It's life or death for them. Just like it is for us.
| Category: Infectious Diseases
March 4, 2004
Steve Postrel of SMU sent along an interesting comment (which he mentions he hasn't fully worked through), one which takes us right back to drug pricing. Yep, to the cheers of some readers and the winces of others. He believes that my reply in the Feb. 22 "Reimportation's Just the Beginning" post doesn't quite add up:
Your correspondent argued that if the US Congress 1) forbade pharmas from price discriminating and 2) defended pharma IP against Canadian infringement then the Canadian government(s) would find themselves paying a higher price and American prices would be slightly lower. You disagreed, on the grounds that:
"The situation in Canada is: would you rather make a little off your drug up there, or make nothing at all? Companies choose the former - there's no way out. Duane's right that in a more rational situation, the balance between the need for profit and the need for the drug would allow things to reach some sort of equilibrium, but I'm not sure that the warm, windless political conditions needed for that state are ever going to exist."
This argument is incorrect given the reader's premise. If price discrimination were illegal, then the pharma's incentives would be transformed--it would have to set ONE price for both countries. Since Canada is so much smaller than the US, the marginal revenue from lowering the price to grab additional Canadian customers would quickly be more than cancelled by the lost revenue due to Americans paying lower prices. Result: The single drug price for both countries is a little bit lower than the old US price if the Canadians are willing to bargain, and the same as the old US price if the Canadians are not willing to bargain (they simply don't get access to these drugs).
The pharmas gain incremental revenue in the first case and lose incremental revenue in the second case. By prohibiting price discrimination, the US would be improving the pharma's bargaining position vs. Canada by credibly committing them not to cut a special deal. It's like visibly welding your steering wheel in a game of Chicken. The only variable here is whether the Canadian authorities would feel politically safe in just refusing their citizens access to new US drugs.
He's right that I didn't fully take in the premise from Duane's original letter, that price discrimination would be made illegal. I've had a couple of other readers suggest something like this, too. I guess my brain refused to process that one, since (from my prespective) right now we're living in a world where price discrimination has been made mandatory (by the countries getting the cheaper end.) It's quite a stretch. But once past that, I think that this argument follows. In an open market, I think that Canadian (and European) prices would come up, and US prices would come down. Steve goes on to say:
There is the potential for a loss of social welfare here, since some transactions benefitting both parties may not happen under the no-price-discrimination policy (if the Canadians are intransigent). This problem is even more severe in poorer countries where prices now are low not because of government bargaining tactics but because of low incomes. Forcing one price for Boston and Benin is going to eliminate transactions in Benin that mutually benefit the pharma and the Beninese patient.
Yeah, that's the flip side of price discrimination, all right. One of my correspondents in the industry once wrote me that we were heading for a world with two kinds of customers, those who won't pay and those who can't. Obviously you'd have to treat those two groups differently. Postrel's suggestion:
Ideally, then, I'd support a policy that made it illegal to price discriminate between Canada and the US, but legal between the US and Mexico or the US and Benin, and that cracked down on reimportation from the latter nations only. The Canadians aren't that poor; they're just using their collective-purchase mechanism to screw the US consumer (and taxpayer) by not paying as much of the research cost of drugs. The same goes for the rest of the OECD. It's time to weld the steering wheel.
I like this idea, as you'd figure. Practical difficulties exist - for example, there's already a problem with the discounted HIV medications going to sub-Saharan Africa. They're being diverted to the grey market in some cases. The incentive to do that will always exist, naturally, as long as there are multiple pricing tiers. But here's a bigger question: would such outlawing of price discrimination be enforcable under US law? And would it be acceptable under the WTO?
| Category: Drug Prices
March 3, 2004
I'm still working on my reply to the Matthew Holt article I mentioned yesterday, so I thought I'd do one of the awful reagents that I spoke of. I'll kick things off with hydrogen fluoride.
The chemically inclined members of my audience might be saying "Hold it! You said yesterday that you'd used hydrofluoric acid!" And that's true, and that stuff is certainly bad enough on its own merits. It gives terribly painful burns, and it eats through glass, to pick two of its fine qualities. But if you're going to be precise, hydrofluoric acid is a water solution of hydrogen fluoride, HF. That's a gas, and it's a lot worse.
Actually, it's just barely a gas. In a cool room it'll condense out as a liquid (it boils at about 20 degrees C, which is 68 F.) The straight liquid must really be a treat, but I've never seen it in that form, and would only wish to through binoculars. It's sold compressed in metal cylinders, like other gases, but it needs some care in packaging. The stuff is so corrosive that special alloys need to be used, usually ones high in nickel. If you stick an ordinary gas regulator on top of an HF cylinder, you're in for trouble, and the complete destruction of the regulator is the least of your worries.
HF has actually been used right out of the cylinder for a long time in Merrifield peptide synthesizers. It's the traditional way to cleave the peptide off the resin at the final step, so there are actually a lot of people who've used the stuff. But it's in a dedicated apparatus that is (that had better be) well sealed, and people treat it with due respect. At a former employer of mine, there was an accident with one of these machines right before I joined the company. The shout "HF LEAK!" went out into the halls, and I'm told that the whole area set a never-to-be-equaled evacuation record. This was one of those drop-things-right-where-you-stand type evacuations, a real sauve qui peut moment.
I've caught some whiffs of HCl, like any chemist has, and it'll wake you up for sure. And I was wrestling with a lecture bottle of HBr gas in grad school, only to have it start to hiss onto my shirt - which was never the same afterwards. But I've never smelled HF, and I hope I never will. As bad as it is on metals and glass, it's much worse on living tissue, although (as I mentioned) a lot of synthetic peptides can stand up to it.
Oddly enough, it's not that strong an acid in the traditional sense. The fluorine doesn't want to let go of the proton enough. It's strong enough to burn, but the big problem is how penetrating it is. As soon as it hits anything moist - like your lungs - it dissolves in the water and turns into hydrofluoric acid again. And that soaks into tissue very readily, with the acid part doing its damage along the way, and the fluoride merrily poisoning enzymes and wreaking havoc. The damage isn't immediately apparent, and there are terrible cases of people who've been exposed and didn't realize it for hours - by which time a lot of irreversible damage had been done.
Fortunately, I have very little cause to even think about using HF. I don't do Merrifield peptide synthesis, and the only times I even use the solution forms of the reagent are on a very small scale and in weakened form (like its complex with pyridine.) Should some lunatic discover a wonderful reaction that requires the gas, I will respectfully pass. As will everyone else.
+ TrackBacks (0) | Category: Things I Won't Work With
March 2, 2004
Little time for blogging the last day or two. I've been finishing up a paper to send to Bioorganic and Medicinal Chemistry Letters, the first one I've written in a while, and I'm checking over another paper that I'm a coauthor on. We're deciding on where to send that one - the lead author suggested Tetrahedron Letters as a possibility, and I thought "Hmm. I haven't had a paper in Tet. Lett. for quite a while." Which was true - a moment later, I realized that the last time was twenty years ago this year! I'm just glad that I usually don't feel as old as that makes me sound. (Talk to me twenty years from now.)
Matthew Holt has a long article on his site that's well worth reading. I'm going to write in response to it this week, because I think a few of its assumptions are incorrect, but it's a good piece nonetheless. It's yet another in the saga of drug prices and research costs, whichs bids fair to be an inexhaustible topic. I am not, though, an inexhaustible blogger. After this round, I'm going to take some time off the topic to recharge my argumentative batteries.
I have a number of other topics backed up in my queue. And I'm going to start off a new occasional feature, a complement to my "How Not to Do It" series of lab stories. This one will be "Things I Won't Touch", and will feature a different reagent each time that I refuse to ever work with. It's a fairly lengthy list, and I'm only a moderately cautious guy. (If anyone else out there has made fluorosulfonic acid from scratch, starting with concentrated hydrofluoric acid and KOH pellets, I'd be glad to hear from you. We can start a club. Admittedly, I was young and foolish at the time, but I made it through without destroying any property. Mostly.)
And one more thing tonight: I'd like to thank everyone for making February by far my highest-traffic month ever. There were about 25,000 page views, which is a roundoff error for the likes of Glenn Reynolds, but thoroughly broke my old record. Much of that was due to my broadside against Gregg Easterbrook, which he certainly seemed to recover from nicely.
+ TrackBacks (0) | Category: Blog Housekeeping | The Scientific Literature