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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png 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: derekb.lowe@gmail.com Twitter: Dereklowe

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March 30, 2006

Give The People What They Want

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Posted by Derek

I get emails every so often from people who are looking for more information about treatments for cancer or other diseases. More often than not, they've come across some Keven Trudeau-like "now the truth can be told" stuff and want to know what I think about it. I should note that almost all of these are non-hostile messages - they're just questions from people who haven't had a chance to learn much chemistry or biology, and want to hear some opinions from someone who has. I answer all of them as best I can.

A common theme in the miracle-cure claims is that such-and-such herb/supplement/device/mystic vibrational ripsnorter "boosts the immune system". If I had a dime for every time that claim is made, I'd be writing this from the conservatory of my mansion, right next to the orchid-hybridizing greenhouse and the frog pond. Who doesn't wish that their immune system worked better, tuned up to where it zapped every virus and cancer cell?

But, as Abel Pharmboy of Terra Sigillata pointed out, you should think twice about asking for that boost:

"Even if such a remedy existed, the immune system is far too complex to regulate with a single, myopic approach due to its multiple checks and balances, feedback loops, and other regulatory process that normally keep us from attacking our own tissue while recognizing and mounting responses against invading organisms. Even the most clever cancer immunologists have only made incremental headway in harnessing immune responses to treat cancer."

He goes on to mention that the notorious TGN1412 antibody was nothing if not an immune booster extraordinaire, and look what happened to the people that were exposed to it. My guess is that most people aren't aware that the immune system can attack a person's own tissues - they figure that there's an infallible friend-or-foe decoder built in or something. No such luck, though, when you consider the number of autoimmune diseases (and the number that might eventually be added to that list).

Comments (9) + TrackBacks (0) | Category: Snake Oil

Missed One!

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Posted by Derek

Sorry about the lack of a post this morning. I took the day off from the Wonder Drug Factory to do some work here at home. Let me just say that if any of you are suffering from an excess of energy, it's nothing that going through a pound and a half of decking screws won't cure.

Comments (0) + TrackBacks (0) | Category: Blog Housekeeping

March 28, 2006

Rioting for Unemployment

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Posted by Derek

From the viewpoint of anyone who's been working in the drug industry here in the US, the riots and demonstrations in France are nothing short of surreal. When they were starting, I had to read several reports before I'd convinced myself that I wasn't misunderstanding things. But yes, these outbursts of rage were being caused by a new law which would allow employers to actually fire workers during their first two years in a job.

Imagine that! When I think about all the restructurings that have been taking place here, I have trouble imagining a world where people basically can't be fired. But I can talk to colleagues in the European drug firms, and hear all about the long, drawn-out negotiations with labor unions, work boards, government agencies and who knows who else that have to take place every time a company contemplates laying off people. They regard all this, naturally enough, as a fact of life. You have to go to the market to get groceries, and you have to go to the airport to fly on a plane. And you have to go to the labor councils and commissions if you want to fire anyone. Where else?

So doubtless there are Europeans who look at the employment-at-will laws in the US and see nothing but heartless anarchy. But what's more cruel? You can tell people that there will be layoffs (to give them time to start looking), then make a clean break of it with a severance package. Or you can announce that there could be layoffs, and follow that with months of wrangling and negotiating, during which time no one knows what's happening.

And the countries that make it almost impossible to fire anyone also (whether their citizens realize it or not) make it almost impossible to hire anyone, either. If you can't unload anyone, you're going to hire very, very cautiously. So during those agonizing back-and-forth months, it's not like there's anywhere else to go. People wander the halls, wondering what's going to happen, knowing there's not much that they can do to help themselves.

This sort of thing is a particularly bad fit with pharma and biotech companies. We're constantly rearranging. Think, for example, of all the small outfits over here in the US that start up and die off every year. I've known people who worked for four different companies in Cambridge and parked in the same lot the whole time. How could you do that in a country that can't fire people?

As irritating as it is, we need that craziness and uncertainty. There are a lot of wild ideas out there, and most of them aren't going to work. Companies are going to flop, merge, stagger around and disappear. But some of them are also going to take off, thrive, acquire and expand, and those will soak up most of the people who were caught in the other upheavals. Even without that sort of turmoil, good people need to know that they're valued, and that they can switch jobs when there's a better place for them to go. At the same time, people who just aren't up to the jobs they were hired to do need, eventually, to be cut loose.

Maybe this is just my American outlook, but I can only think that an economy with that can absorb those kinds of risks (and seek those kinds of rewards) will outcompete one that tries to buy its way to safety.

Comments (36) + TrackBacks (0) | Category: Business and Markets

March 27, 2006

Cleaning Out the Hood: An Internal Monologue

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Posted by Derek

Man, is this hood of mine scuzzy. . .these things suck in dust all day long, and it all piles up in layers on the bottom. Spilling silicone oil back there doesn't seem to help much either, gotta say. Of course, if all the dust from the lab is being pulled in here, where's all of the dust out on my bench coming from, eh?

And this two-liter round-bottom flask, which has its share on it: that's from, like, 2003 or so. The project before the project before the project before this one. Give or take. I really should get this stuff out of it, but there must be fifty or sixty grams in there. And scraping that out would be a nightmare. And dissolving it wouldn't be a lot of fun, either. And I'm not completely sure that I remember what the stuff is. Argh.

Then there's this rig back here, my phosgene trap. I can get that out of here, 'cause with any luck I'll never have to use phosgene on that scale again. Of course, as soon as I break it down and clean it, someone across the hall will discover the New Wonder Lead Structure on our project, something so hot that we all have to switch over and start working on it, and the second step to make it will require a bucket of phosgene. Never fails. I haven't been doing this for seventeen years for nothing, y'know.

Or have I? You'd think by this time I'd learn to label flasks like this one over here. Those sure are some nice crystals. Makes me think that they must be leftover sodium sulfate or something. Take a bit out and see if it's water-soluble - if it is, it's junk, 'cause I haven't made anything water-soluble in I don't know when. Where were crystals like these when I needed them, back in grad school? Kept trying to grow some for X-ray work, and all I could get were these fluffy little needles, fine as frog hair.

This, on the other hand, is not as fine as frog hair. Look at that - whatever this brown junk in here is, it sure isn't doing that rubber septum on top any good. Live an evil life, and you'll come back as a rubber septum. Or maybe a vacuum pump trap. Oh yeah, that's that chlorosulfonic acid reaction. No wonder the septum looks like that. Reaction didn't do a thing, though - how can you heat something up in neat chlorosulfonic acid and not have it do something? Against the laws of nature, that is. But you know, taking grief from Nature is kind of the job description around this place. . .

Comments (9) + TrackBacks (0) | Category: Life in the Drug Labs

March 26, 2006

A Word to the Wise About TGN1412

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Posted by Derek

Here is the voice of someone who is under a great deal of stress and is not thinking clearly:

Thomas Hunig, the German professor who founded the TeGenero company, said he still hoped the drug, TGN1412, could be brought to the market.

He said he was devastated that the six men were taken ill but said that he was "not going to give up".

Professor Hunig said: "I do hope TGN1412 can come to the market. This tragic incident does not exclude the theoretical application of TGN1412 some time in the future.

Let me be one of the voices informing Prof. Hunig: there is an almost overwhelming likelihood that his drug will never again come near a human being, much less near the market. Pharmaceutical companies drop compounds all the time that show far less severe side effects than this in rats - a disaster like this in man is the end of the line. That's not to say that the whole idea of a CD28-derived drug is dead (although it's going to be slow going after this), but TGN1412 is not going to be it. Go look for a clinical supervisory board - outside of North Korea, that is - that would allow another dosing in humans. Good luck.

Says Prof. Hunig:

""I don't want to hurt anybody in any way. I don't want to come across as a crazy scientist who wants to save his baby despite the victims he has taken. Definitely not."

Someone needs to point out that he's doing a pretty poor job of not coming across like that. Talking about the wonderful science involved and all the work that's gone into the project doesn't help, either. Arguments about how much time and effort have been spent are irrelevent - that's a sunk cost if ever there was one. And the science is no doubt nifty in the extreme, but our scientific understanding of the drug and its effects is clearly a bit. . .incomplete, which places an upper bound on just how nifty it can be.

I feel like the guy in the Monty Python sketch: Dr. Hunig, your drug has ceased to be.

Comments (23) + TrackBacks (1) | Category: Clinical Trials

March 24, 2006

Explosion News

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Posted by Derek

It's a busy news day. Word is this morning (EST) that there's been a huge explosion at a chemistry building at the ENSC of Mulhouse, in Alsace in eastern France - an old and well-known chemical engineering school. One faculty member appears to have been killed, and there are several injuries. The building looks to have been severely damaged, and local residents are saying that the explosion was heard all over town and felt like an earthquake.

I've been looking at some news reports, but no one's reporting on what caused the blast. This sounds like much more than a typical batch-of-something-in-the-hood going up, though, that's for sure. If any readers can shed some technical light on this in the comments, I'd be grateful.

Comments (5) + TrackBacks (0) | Category: Current Events

Can You Say "Uebernahmeangebot"?

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Posted by Derek

Merck KGaA made a bid for Schering AG a little while back, which is one of those pharma news items I never got around to talking about here. I have to put those German initials in there, because (just to confuse people who don't follow the pharmaceutical industry) those two companies have no connection with the US Merck of Vioxx fame or with Schering-Plough. Well, no connection since the First World War, anyway, when the US seized their assets here and split them off into new companies. A lucrative sideline would consist of being paid a dollar every time someone mixes these up.

At any rate, Schering AG sneered at the offer, saying that Merck valued their company far too cheaply. My usual response to things like this is to wonder, then, how such a bargain could be just sitting there on the open market without anyone realizing it, but hey, I'm not an M&A guru. (And you can make an argument that the German stock market doesn't do as good a job at valuing companies as the US ones, because German firms have traditionally not raised as much money through sale of stock. German stocks are a different world - note that the "German NASDAQ", the Neue Markt was closed in 2002 after only five years of trading. Germany basically experienced the dot-com boom through an entire stock exchange of its own).

Well, things were quiet on the merger news for a little while, until Bayer popped up last night with a higher bid for Schering AG. They seem to have thought that As of this morning, the press is reporting that Merck has pulled out of any possible bidding war, which no doubt leaves them wondering just what to do now, and leaves Bayer and Schering's people all wondering what just happened. Are other small-to-medium European pharma outfits (Novo Nordisk, Akzo Nobel, Solvay, Altana and so on) ready for some action of their own?

Comments (7) + TrackBacks (0) | Category: Business and Markets

March 23, 2006

Crystals of Doubt

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Posted by Derek

Here's a limits-to-knowledge post for you. On Wednesday, when I was cranking out a batch of an intermediate we're using these days, I needed to separate two fairly closely related compounds (which I'll call A and B) from each other. One surefire way to have done that was chromatography, but I just didn't have time for that. While I was rota-vapping down the mixture, I noticed that some white crystals were starting to come out of the methylene chloride solution, so I took the flask off and checked a small sample of the solid. Sure enough, it was pretty pure A, so I filtered that off and continued.

Taking out all the solvent left me with more white stuff, which was mostly B, with some A still hanging in there. In the past, we'd purified B by crystallizing it from another solvent mixture (ethyl acetate/hexane, the first combination the lazy - or just plain experienced - organic chemist reaches for). So I tried that out, dissoving the solid in a small-to medium amount of hot ethyl acetate, then adding hexane while it was still warm. I cooled the solution down by dipping the flask in ice water until it had come down to about room temperature, and was swirling it around when suddenly it starting snowing white powder. Ta-daa! A check of this stuff showed that it was almost completely pure B. The solution, for its part, was now a majority of A with some B left around. I took what I had and ran with it - this was one of the bird-in-the-hand situations, because people were waiting on this stuff.

My point is that such things are almost completely empirical. I've never heard of anyone who could predict from first principles what solvent system to use to get something to crystallize. I'd be tremendously impressed if anyone could take the structures of my two compounds, feed them into a dissolvo-matic program and announce "Yep, methylene chloride for A, and ethyl acetate-hexane for B. That'll do the trick."

As far as I know, there's no such thing, and no one is even close. I'd be glad to hear if I'm wrong. But if we can't predict, even just in rank order, what solvents will dissolve (or crash out) a given molecule, just how good is our molecular modeling, anyway?

Comments (8) + TrackBacks (0) | Category: In Silico

March 22, 2006

A Lengthy Day

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Posted by Derek

Well, it was a long day at the Wonder Drug Factory - I got in early to start a large reaction, and took it through a workup and column during the rest of the day. I'm taking tomorrow off to take my kids out and around, and since people were waiting on the stuff I made today, or so I'm told, there had better be something missing from the batch when I come back. (Of course, I don't have much room to get haughty, since the reason that there's a shortage was because I made the wrong isomer of the stuff by mistake last time. Ah, how we laughed, except me.)

So rather than crank out something aggressively substandard tonight, I'll leave everyone to their own devices. A run up and down the blogroll at left should be enough to impair your productivity - I'll see everyone on Friday.

Comments (1) + TrackBacks (0) | Category: Blog Housekeeping

March 21, 2006

Nitromed's Slow Decline

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Posted by Derek

Nitromed is a company whose fame, such as it is, comes from the controversy over BiDil (which I wrote about here. It's a mixture of two generic hypertension drugs which more or less flunked the main parts of its original clinical trial, except in the cohort of black patients. You can get burned by subgroup analysis, but Nitromed persevered and last summer won approval for what was probably the first race-based pharmaceutical.

The problem is, it's expensive to launch and promote a drug all by yourself, and BiDil turned out not to sell the way that optimists both outside and inside the company had hoped. The company has had a hard time convincing health insurance organizations to pay for the drug, and they've made noises about how their contract sales force hasn't performed up to expectations. Nitromed hasn't made a dime of profit since BiDil came on the market. The stock was at about 19 when the FDA approved the drug late last June, and rose as high as 24 and change a month or so later. Since then, though, it's been a long, slow slide downhill. (Try Google's new finance section for a neat chart). One wonders if they were able to unload a proposed stock sale back in January at their planned price or not.

Today came the abrupt word that the company's CEO and CFO have resigned, no reasons given. But no reasons had to be, did they? The stock's been rising a bit, apparently from bottom-fishers hoping for a takeover. But who's going to do that? BiDil really doesn't look like a winner so far, and I don't think the company has all that much more to offer besides hopes and dreams. Doubtless many of these research areas took a hit while all the money was spent launching BiDil . If the company has anything else ready for the clinic, I sure haven't heard about it, and the way that web page trumpets their IP rights isn't a good sign. If there were anything else to brag about, that wouldn't be the headline, would it?

Nitromed reminds me of the old story about the fellow who lost three cars playing poker and drawing to inside straights. He lost the first two by not filling his hand - and lost the third one by making the straight. Getting BiDil to the market may have been the company's biggest mistake.

Comments (10) + TrackBacks (0) | Category: Business and Markets | Cardiovascular Disease

March 20, 2006

Grad School, Blogged

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Posted by Derek

I spent the day giving the Wonder Drug Company good value for their money - cranking out a load of intermediate for other folks on the project and getting analytical data on some other samples. And talking about that sort of thing reminds me to link to a chemistry blog that I wasn't aware of until recently: a grad student named Dylan Stiles, who's working for Barry Trost out at Stanford.

Stiles is running just the kind of blog that I would have if. . .well, if the Web had existed back in 1985 when I was a grad student. Actually, it was probably a good thing for my graduate career that it didn't, come to think of it. That's the era of the "old timey" NMR machine in this post of his, which makes me wish I could find a photo of what we considered an old-timey machine. Ah, here we go: scroll down to the middle of the page, to the picture under "1976-1977". I used one of those things, and no, you didn't have to load coal in the back of it and wait for the boiler to fire up. It just looks that way.

At any rate, Stiles talks about the reactions he's running, with drawings and schemes, and takes photos of the crystals he gets and other oddities around the lab. I really wish I could do something similar once in a while. I obviously can't talk much, though, about (for example) the heterocycle I finished up today, except to note that the reaction used an unseemly amount of straight hydrazine, like nearly half a liter, and I was very glad to see the back of it. And I'd like to show some photos, too, but the Wonder Drug Factory has a "no camera" policy, and I can see why, what with chemical structures drawn all over the place.

But there would be some things to show off: I dropped a big stirbar right through the side of a one-liter pear-shaped flask the other day, for example, producing a perfect Pyrex analog of a gourd birdhouse. All I need to do is flame-polish the hole and find a way to stick a stopper permanently into the ground glass joint, which is a task that I've always seemed to be pretty skilled at, and I'm in business. See what you're missing?

Anyway, give Stiles a look if you're a hard-core organic chemistry geek like me, and if anyone knows of some other chemistry grad student or post-doc blogs, please send them along. I need to differentiate my blogroll a bit more, and that would be a fine category to have.

Comments (5) + TrackBacks (0) | Category: Graduate School | Life in the Drug Labs

TNG1412: Was There a Warning?

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Posted by Derek

When everyone first heard about the TeGenaro/TGN1412 Phase I disaster, the immediate question was whether it could have been prevented. As mentioned before, the main problem I had was that the volunteers seem to have been dosed fairly quickly, rather than waiting longer to see how the first patient did. That alone would have contained the tragedy to one person. But even then, we'd all be asking how that one case could have been avoided. I'm not well-versed enough in immunology to say for certain, but according to the Times of London, there's some earlier work that might have given everyone pause if it had been sufficiently appreciated.

They quote Angus Dalgleish, a British professor of immunology, as saying that he was amazed that the TGN1412 trial had been allowed, considering that at the ASCO meeting last year, a team from the National Cancer Institute presented the results of a study of an anti-CLTA4 antibody in cancer patients. They didn't see the catastrophic results of TGN1412, but the trial was rough enough. Nearly half of the patients in the high-dose group saw a harmful immune response - most of them recovered, but one needed surgery. That target is another receptor on the surface of T-cells, and it's involved in the same general activation/deactivation pathway that CD28 (TGN1412's target) is. CLTA4 activation blocks the activating effect of the CD28 pathway - in fact, it's only induced after the CD-28 receptor has been stimulated, and it seems to come on in order to damp it down. Immunology's full of these reverse-reverse things.

So one net result of either approach is to enhance CD28 signaling - TeGenaro's antibody strongly activates CD28 directly, and Medarex's inhibits its inhibitory pathway. Still, the two therapies were aiming at opposite endpoints: TeGenaro was mainly hoping to enhance the activity of regulatory T-cells (which would then decrease autoimmune activity) while the NCI group was hoping to generate a stronger overall immune response against renal tumors. Of course, it looks like the "stronger overall immune response" part of this pathway wins out.

Here's the abstract from the meeting, which tells us that the anti-CLTA4 antibody they're talking about is MDX-010, from Medarex. They've been working on it for years, and have (for example) reported similar results in 2004 in a study against metastatic melanoma. Their first attempts in this area were reported in 2003 in PNAS.

And it's still being studied - in fact, it's one of the more advanced things in Medarex's pipeline. Here's a trial that's in recruitment right now for late-stage melanoma, in combination with a potential melanoma vaccine, MDX-1379, and here's one for prostate cancer, in combination with androgen therapy. They wouldn't have made it to Phase III with this if they'd constantly seen the kinds of effects reported by the NCI group.

So the Times article is semi-right, although it gives the impression that there's this one study from last year that should have definitely raised the warning. But anti-CLTA4 therapy has been around for several years now, and it's well-represented in the literature. And it's still in advanced clinical trials, to boot. This is the sort of thing that both TeGenaro and the review board that approved its study would have been well aware of, and would have taken into account. It now appears that blocking CLTA4 is something that has to be approached with caution, while activating CD28 directly is disastrous, but I'm not sure that was obvious before this trial.

Comments (7) + TrackBacks (0) | Category: Clinical Trials

March 17, 2006

Update on TGN1412

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Posted by Derek

I don't often do updates on the weekends around here, but I wanted to point out this update from the BlackTriangle blog in the UK on the TGN1412 antibody trial. Anthony Cox has all the latest information from the medical and the British press, including many details which haven't been mentioned in most reports.

For one thing, it's now being said that not only were the primate tests clean, but these first-in-man doses were set at 1/500th of the primate dose. As the latest articles in Nature and New Scientist show, there are plenty of immunologists around who are expressing doubts about TeGenaro's therapeutic approach. But it's hard to say how much of that is ex post facto - after all, a review board signed off on this, and they presumably included some competent people.

My guess is that it's going to be a long time before anyone tries another immunomodulatory antibody in humans. . .and it wouldn't surprise me to learn that it's going to be more difficult to recruit for many Phase I trials in general. That isn't good.

Comments (16) + TrackBacks (0) | Category: Clinical Trials

March 16, 2006

Price Gouging or Not?

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Posted by Derek

Update: More on this issue from Jim Hu here.

The New York Times ran a pretty heavy-duty article the other day on drug pricing. But for once, it wasn't the big companies that were getting pummelled. No, this time it was Ovation Pharmaceuticals getting the treatment, and I'd have to guess that most readers will have the same reaction I did: who they?

Well, they're sort of a specialty generic company. Their business model seems to be taking on ancient medications, which other companies are giving up on, but which still have a small patient population to serve. Their business model is also apparently to raise the price of said drugs, and that's what got them into the papers:

"Last August, Merck, which makes Mustargen, sold the rights to manufacture and market it and Cosmegen, another cancer drug, to Ovation Pharmaceuticals, a six-year-old company in Deerfield, Ill., that buys slow-selling medicines from big pharmaceutical companies.

The two drugs are used by fewer than 5,000 patients a year and had combined sales of about $1 million in 2004.

Now Ovation has raised the wholesale price of Mustargen roughly tenfold and that of Cosmegen even more, according to several pharmacists and patients."

Mustargen is better known to chemists as nitrogen mustard, which was basically the first chemotherapy agent ever used. Cosmegen, for its part, is the brand name for actinomycin D, which goes back almost that far itself. (To give you the idea, the first person to try it out for cancer was Sidney Farber, whose last name still turns up in cancer therapy circles.

These are drugs from the caveman days, that's for sure, and many references (that Wikipedia link to nitrogen mustards, for example, unless it's been fixed by now) will tell you that they aren't used at all any more because of their toxicity. But they're each still useful for the small group of patients the Times article mentions, generally those with very particular forms of cancer that respond well to these agents above all others. To give you the idea, five thousand patients is one fortieth the market size for what the FDA considers an orphan drug, and it's not clear if that's the patient population for both drugs put together. These are orphaned orphans.

This article is of a piece with the recent one on the price of Avastin, which I spoke about here:

The increase has stunned doctors, who say it starkly illustrates two trends in the pharmaceutical industry: the soaring price of cancer medicines and the tendency for those prices to have little relation to the cost of developing or making the drugs. . .people who analyze drug pricing say they see the Mustargen situation as emblematic of an industry trend of basing drug prices on something other than the underlying costs. After years of defending high prices as necessary to cover the cost of research or production, industry executives increasingly point to the intrinsic value of their medicines as justification for prices."

Now we're down to the real question: is this price justified, or not? Ovation is in business to make money, like any drug company, and charging a high price is about the only way to do that when you're talking about a few thousand patients. A company like Merck could carry these things on its books without much harm being done to its bottom line, because the costs of its other medicines would make up for them (not that the Times is too crazy about those other prices, either). But when a small company like Ovation takes them over, they're going to try to make them into profit centers. Over at Blogs for Industry, Jim Hu asks: "I wonder what (the Times) would be writing if Merck just dropped Mustargen and these patients weren't able to get it at all." He's got a point.

For the most part, Ovation seems to be getting the prices that they're asking. One problem is that they're selling injectable Mustagen, which is the approved form, but there's one set of patients that uses the stuff as a topical lotion (which is formulated for them by local pharmacies). It's harder to get insurance to pay for that, since it's not an approved use. (And it's hard to imagine who would be able to go to the expense of getting it approved, either, considering the subset-of-a-fraction-of-an-orphan size of the market). These people are really feeling the price increase, and the Times article accordingly spends most of its space on them. Ovation is apparently lobbying for increased insurance coverage - which is, after all, in their financial interest - but for now, things don't seem to have changed.

The downside, for Ovation and for the industry, is that this kind of thing makes it very easy to write the heartless-price-jackers article. And this is why I think the ban on Medicare using prices as a consideration is a mistake. I know that my industry lobbied hard for it, and it's no mystery why. But I'd rather have Medicare responding to (and giving out) pricing signals, and I think that (for their part) private insurance companies should do so at every opportunity. Says the Times article:

And once a company sets a price, government agencies, private insurers and patients have little choice but to pay it. The Food & Drug Administration does not regulate prices, and Medicare is banned from considering price in deciding whether to cover treatments.

While private insurers can negotiate prices, they have limited leeway to exclude drugs from coverage based on price, said C. Lee Blansett, a partner at DaVinci Healthcare Partners, which works with drug makers on pricing and marketing.

"Price is simply not included in whether or not to cover a drug," Mr. Blansett said.

But why not? It's included as a factor in decisions to pay for all sorts of other things. If that quote were talking about anything other than pharmaceuticals, it would sound weirdly obvious. The same goes for that earlier excerpt: all sorts of things are priced considering factors other than their intrinsic costs. (What the market will pay, for example). Competing on price sounds heartless at first, but consider: if Ovation's raising their prices too high, that should open the door for someone else to step in and undercut them. Pricing signals go both ways. . .

Comments (9) + TrackBacks (1) | Category: Cancer | Drug Prices

March 15, 2006

No Immunity From Immunity

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Posted by Derek

(Update, March 17: See also later entry here.

There's been a severe problem with the first-in-man dosing of a new antibody in England. TeGenero, a small company in Germany, was testing their most advanced candidate, TGN1412, which is a monoclonal antibody against CD28. That's a glycoprotein on the surface of many types of T cells, and it seems to be extremely important in several mechanisms that activate them. Accordingly, finding something to modulate its activity would seem to be a promising way to attack autoimmune and other inflammatory diseases.

But when TGN1412 went into six volunteers in Phase I this week, all of them ended up in the hospital, and two of them are gravely ill. The press reports make it seem like some sort of anaphylactic reaction, but it sounds like they're not treating it like simple anaphylaxsis, so there must be something more going on. That's a very surprising outcome, since if anything you'd expect the immune response to be downregulated in response to the drug. (Update: this is only partly true - see end of post.) But there's an awful lot about human immunology that we don't understand, to put it mildly. TeGenero says that:

"These events were completely unexpected and do not reflect the results we obtained from initial laboratory studies which enabled us to progress investigations into human volunteers. . .The drug was developed in accordance with all regulatory and clinical guidelines and standards. In pre-clinical studies, TGN1412 has been shown to be safe and the reactions which occurred in these volunteers were completely unexpected”

I have to believe that this is correct. Neither TeGenero, the company conducting the trial for them (Parexel), or the British regulatory authorities have anything to gain from taking a drug into humans that had shown severe effects in animals, despite rumors to the contrary that seem to be going around in England. There's a breathless report in The Independent (I know, that's redundant) to this effect:

"The men, who were offered £2,000 to take part, were recruited by the US company Parexel, for the trial in its 36-bed unit on the Northwick Park hospital campus. They reportedly signed a contract warning that side-effects in rats and mice included "increased urine volume, decreased faeces, redness of the skin". Dogs experienced "increased heart rate and decreased blood pressure"."

I have news for the Independent, though - if we killed off every drug that showed effects like this, we'd never take anything into humans at all. The dog cardiovascular effects would be worth checking out in detail before going forward, naturally, but that's what dogs are for, to show you cardiovascular side effects. And I note that none of these effects have anything to do with devastating immune reactions. If that's all that TeGenero saw in the animal studies, I can see why they were shocked at the human results.

But antibodies are powerful - no one should forget that. Every antibody therapy has a small but real risk of setting off something terrible, and if you're targeting the immune response itself, well, the risk just goes up. The immune system is a bit like demonlogy: don't call anything up that you don't know how to send back down. Unfortunately, we don't know many effective spells yet.

My sympathies go out to those affected and their relatives and friends, of course. They shouldn't, as far as I can see, torture themselves thinking that this could have been foreseen. I hope that everyone makes it through.

Update: I've inadvertently glossed over some of the mechanism of TGN1412. Its binding to CD28 actually sets off the receptor's signaling - it's an antibody agonist. This makes it a T-cell activator, but it seems to particularly activate the class known as regulatory T-cells. These are modulators of the activity of other classes of T-cells involved in autoimmune responses.

So there's a way that things could have gone wrong - if TGN1412 isn't quite as selective in the real-world human immune system as it is in the animal models. Alternatively, even if it is selective but the spectrum of human T-cell response to CD28 ligands is intrinsically somewhat different, things could have gone off the rails very quickly. There appears to have been little reason to suspect either of these possibilities going into the clinic. We're going to learn something important about human immunology from this incident, but this is certainly a hell of a way to do it.

More: BlackTriangle has a roundup of some reactions in Britain.

Comments (20) + TrackBacks (2) | Category: Clinical Trials

March 14, 2006

Neowater Replies

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Posted by Derek

I received (some time ago) an answer from Miguel Cizin and the folks at Docoop, makers of Neowater. (If you haven't seen the first parts of this story, they're here and here). In that last post, I had a number of look-under-the-hood physical chemistry questions about the stuff, in an attempt to figure out if there's anything to it or not. Here they are in order, with the provided answers:

1. How much of Neowater's characteristics can be explained under the usual framework of colligative properties? That is, by how much is the boiling point of Neowater elevated, and by how much is its freezing point depressed?

The company provided some differential scanning and isothermal titration calorimetry data in response to this, which I appreciate. I'm no expert in this area, but to my eye the ITC plots look broadly similar, but with a noticeably longer half-life to thermal equilibrium in the Neowater runs. (It's not noted what substance was being injected in these experiments).

2. Similarly, what's its vapor pressure at STP? Does it show a negative deviation from Raoult's Law (as you'd expect from the descriptions in the patent of Neowater's structure), and is this deviation much greater than expected given the low levels of particulate matter contained? The literature on the DoCoop web site, I should note, mentions that Neowater evaporates more slowly than regular water.

DoCoop replies: "Neowater indeed evaporates more slowly than regular water, since the water molecules are less available as they are attracted to the charged nanoparticles, hence it takes more energy to dislodge them. The difference in the vapor pressure is one of the mechanisms of action that we use to alter the dynamics of reactions to benefit our customers. You are right, there is a difference in the vapor pressure indeed. We will not enter here into the metrics or actual values, since it is proprietary for use by customers, so we focused our answer on the claim itself only, rather than the detail, and hope you understand us." This isn't as complete an answer as I'd wish for - in fact, it doesn't add anything at all to what we've already been told, and I have a hard time believing that a deviation from Raoult's Law is proprietary information. But we'll let that go for now.

3. In the same vein, what's the surface tension of Neowater as compared to the water it's produced from? I could imagine it going either way - if large clusters of water are occupied around the nanoparticles, the surface layer of water may not form in as ordered a fashion, leading to lower surface tension. On the other hand, if Neowater is better thought of as a collection of larger polar "balls" of hydrated particles, perhaps the value could end up higher.

Answer: "Exactly as you stated above. This is another mechanism of action in Neowater that we use to the benefit of our customers for the enhancement of their reaction. In Neowater, the dynamic range of surface tension is +15% to -15% around 72 dyn."

Actually, I think that should be dyn/cm, and that value is smack on top of the normal values for water (between 72 and 73). We're left to wonder what could cause it to vary higher and lower, though, and to wonder which of my explanations were correct. The DoCoop website has a picture of the stuff on a hydrophilic surface, showing a higher surface tension. I should note that if you want lower values, a drop of detergent will do the job nicely.

4. What's the conductivity of Neowater as compared to its untreated form? How does it change in the presence of small amounts of electrolytes as compared to regular water?

Answer: "Neowater's conductivity is like that in RO or distilled water. Neowater has no ions. It will change if (they're added). We are in the process of starting a research project with a NJ-based University on this application for batteries."

5. Have the rates of standard nucleophilic displacement reactions and/or cycloadditions been measured in Neowater? The presence or absence of a polar transition state and the resultant effect on reaction rate would make an interesting test of its properties. (Neowater is stated to be a "more hydrophobic" form of the liquid). Which reminds me: have Neowater's dipole moment and dielectric constant been determined?

Answer: " Neowater is an irregular media from the point of view of nucleophillic and cycloadditions. We did not find the right method to characterize this irregularity. We are open to suggestions because one of our business opportunities is in crystallization of proteins, where this issue is central. We do see irregularities of the nucleophilic behavior in Neowater with our university partners that are developing this application at the Weizman Institute in Israel. Regarding the dielectric constant measurement, there is a change in it in Neowater vs. regular water. We could not conclude yet the correlation b/w the shift in the structure of the "spinnor network" within Neowater if this is what you are trying to understand."

I would think that if you have a system that shows that Neowater is an "irregular" medium, then you'd have a method to begin characterizing it right there. But I'll wait to see if something comes out of the Weizmann work. For cycloadditions, I'd suggest looking at some of the aqueous Diels-Alder work from the 1980s.

And as for my question #6, about whether deuterated Neowater had been prepared, the company indicates that it hasn't done anything in that direction yet, although they are looking into the idea of using Neowater as an MRI contrast agent.

So, where does this leave us? While I appreciate the company taking time to answer my queries, I can't say that I'm all that much more informed compared to what I'd been able to find out from their press releases. That's clearly the way that they'd like to keep it, which is naturally their right from a business standpoint.

But from the scientific end, I have trouble buying into this "It's all proprietary for the use of our customers and the enhancement of shareholder value" explanation. Because if Neowater were really the sort of breakthrough that DoCoop's material makes it sound like, it would be worth a slew of research papers which would give it more scientific credibility. And since the company has already worked to secure its patent rights, such papers would certainly be feasible - desirable, even, considering the publicity that would follow.

And besides, if you want to know about the effects of nanoparticles in water, you can turn to the people who actually do publish their results. Perhaps any rate enhancement in PCR runs with Neowater is due to enhanced thermal conductivity - after all, temperature cycling is an essential part of the technique. How did I come to this conclusion? By reading this paper on the effects of aqueous nanoparticles on PCR reactions. It's a perfectly reasonable paper, and contains, as far as I can see, more data than DoCoop has ever released.

While we're on that subject, here's a site that will tell you so much about the effect of nanoparticles on thermal conductivity that you'll wish you'd never asked. Similarly, if you'd like to know more about the effect that nanoparticles have on water's surface tension, you could go here. If you wanted to learn more about the properties of water confined to nanoscale environments, you'd get a lot more out of this guy or this one than you would out of DoCoop's literature and patent filings, not that that would be very difficult.

So, all in all, I continue to be not very impressed. If Neowater were the kind of wild breakthrough that the company claims it to be, it would be worth more than its current use as a sort of STP-oil-treatment for PCR reactions. The company can, of course, have the last laugh on me over the next few years, and I wish them luck in doing so. But I'm betting that any breakthroughs in the aqueous nanoparticle area will find their way into the scientific literature in a more convincing fashion.

Comments (10) + TrackBacks (0) | Category: Biological News

March 13, 2006

The Big Statin Pillow Fight

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Posted by Derek

The American College of Cardiology meeting in Atlanta is the source of all those news headlines today on cholesterol-lowering drugs. It can hard to make sense of all the studies that are being reported - my favorite confused headline so far is "Merck Says Vytorin Beats Zocor", to which the appropriate response is "It had damn well better". Beating Zocor is the whole reason that Vytorin exists, since it's Zocor (simvastatin) plus Schering-Plough's dietary cholesterol absorption inhibitor Zetia (ezetimibe).

The cholesterol-lowering market has long been vicious, but it's getting more so. There's a simple reason: Zocor's going generic this summer. Many managed-care organizations are looking forward to moving patients to the new, cheaper statin as soon as that happens, and companies are trying to come up with reasons to keep that from happening. Merck needs to show that they've got something better than their old drug, and other companies with their still-patented statins want to show that they do more than the generic will, too.

Thus AstraZeneca's big splash with their results for Crestor (rosuvastatin), where they showed arterial plaques actually reversing and getting smaller. I realize that drug-company-sponsored results aren't exactly in the highest standing these days. But the lead investigator on this study was Steve Nissen of the Cleveland Clinic, who is not exactly a tool of the drug industry, unless someone's updated the master list without telling me.

And that's clear from his own comments on the results, as opposed to those in the AstraZeneca press release. While impressed with Crestor's efficacy, Nissen did a good job putting things in perspective.

For example, he points out that he doesn't think that much more plaque shrinkage is even theoretically possible - most of the lipid content of the plaques has probably been taken out by this point. And he also mentions that no, this trial wasn't powered to say whether this effect actually improves long-term morbidity and mortality in patients (although you'd have to think it would, at least a little bit). Most tellingly, he makes the observation that everyone else's statins probably do the same thing if dosed to give a similar degree of cholesterol lowering.

AstraZeneca's argument has long been that gosh, nothing can lower cholesterol like Crestor, and I'm sure that much more in this line is coming. And Merck and Schering-Plough will continue to beat the drum for Vytorin, while Pfizer will never be known for their coyness about the benefits of Lipitor. But the Zocor patent expiration is just a coming-attraction trailer for this market. Its run as the cheapest effective statin in town will go on, arguments and advertising blaring all around it, for about three or four more years. And that's when Lipitor starts going off patent. You can bet that studies are already under way to try to show why people shouldn't switch to its generic when the time comes. . .

Comments (7) + TrackBacks (1) | Category: Cardiovascular Disease

March 12, 2006

Bubble Fusion Implodes

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Posted by Derek

The bubbles produced by sonication of liquids are weird things, and there's no doubt that strikingly high temperatures and pressures can be produced in them (for strikingly short periods of time). The idea that they might be high enough to induce nuclear fusion has been around for years, and in 2002 a group at Oak Ridge claimed to have done it. (I wrote about that on my old site here when the news came out, and here a few days later).

In 2004, a further paper from the group came out, followed by another one in January of this year. The lead investigator, Rusi Taleyarkhan, had moved to a new faculty position at Purdue, and a number of people there were working on the idea. I was encouraged. Perhaps I shouldn't have been. Nature is now reporting that many people at Purdue have extreme doubts about Taleyarkhan's work. And if these accounts are accurate, I don't blame them:

Once Taleyarkhan had arrived, lab members became increasingly concerned by his actions. Jevremovic says that he would sometimes examine the equipment and claim that it was producing positive results, referring to an oscilloscope that he had. She says that she was uncertain about how the oscilloscope fitted into the experiment so she asked him for the raw data, but never received any. "He said: 'Look, there's a peak', but there was nothing to see," she says. "I started questioning it."

Then one day, in or soon after May 2004, lab members arrived to find that Taleyarkhan had removed the experimental set-up from the communal lab, and taken it to his own lab off-campus. "I was really upset," says Jevremovic, who had been planning further work with the equipment. . .

Meanwhile, the data in the latest paper have come in for some very hard scrutiny. The experiments are claimed to emit neutrons at the particular energy that would be a sign of nuclear fusion, but it seems that the published data aren't consistent with that at all - and are consistent with those from californium-252, which is a common neutron source. There wasn't supposed to be any such source in these runs, though, which is very disturbing. (A preprint of the paper on these problems is here, for those who want all the details.

I Am Not a Nuclear Physicist, but I am a scientist, and this is all starting to look very sad and suspicious. Depressing as it is to write this, I'm now strongly inclined to think that the Taleyarkhan work is spurious. It would take some amazing results to convince me otherwise, and this would be a mighty good time for him to produce them if he's got 'em. But I don't think he does. As I've said before, the possibility of discoveries like this fills me with joy, which makes it still more painful to watch it all crash in a flaming heap.

The idea of sonochemically induced fusion isn't dead: others are looking at it in different systems. Sonication bubbles are indeed weird (see also here), and much remains to be discovered about them. But a lot of time and effort has seemingly been wasted on the wrong approach, and the whole field ends up looking like a refuge for cranks. It's sad, it's just sad.

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March 9, 2006

Wonder Drug, Indeed

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Posted by Derek

"Wonder Drug Inspires Deep, Unwavering Love of Pharmaceutical Companies":

"Many individuals today lack the deep, abiding affection for drug makers that is found in healthy people, such as myself," Pfizer CEO Hank McKinnell said. "These tragic disorders are reaching epidemic levels, and as a company dedicated to promoting the health, well-being, and long life of our company's public image, it was imperative that we did something to combat them". . .

. . .PharmAmorin is the first drug of its kind, but Pfizer will soon face competition from rival pharmaceutical giant Bristol-Myers Squibb. The company is developing its own pro-pharmaceutical-company medication, Brismysquibicin, which will induce warm feelings not just for drug corporations in general, but solely for Bristol-Myers Squibb.

Now that last one would be a real challenge. Of course, you've got to wonder what your rodent efficacy model for something like this would be. . .

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Men and Women and Science and Jobs

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Posted by Derek

That Greenspun piece that set off so much comment around here was ostensibly addressed to the position of women in science, but didn't have much specific to say on the topic. So I thought I'd mention another article, by Peter Lawrence of Cambridge in PLoS Biology, that deals with the subject more directly.

We're heading into the territory that got Larry Summers in so much trouble at Harvard, but here goes. The first part of Lawrence's argument is that it's silly to assume that men and women are interchangeable. As it happens, I agree with him:

Some have a dream that, one fine day, there will be equal numbers of men and women in all jobs, including those in scientific research. But I think this dream is Utopian; it assumes that if all doors were opened and all discrimination ended, the different sexes would be professionally indistinguishable. The dream is sustained by a cult of political correctness that ignores the facts of life-and thrives only because the human mind likes to bury experience as it builds beliefs. Here I will argue, as others have many times before, that men and women are born different.

By this point, some people usually will have already stomped out of the room. But wait - that word "different" has to be peeled away from the words "better" and "worse". Allow me a chem-geek analogy: lithium and sodium, though similar compared to most other elements, are still clearly different from each other. Which one is better, which worse? The question makes no sense, but that's exactly where many arguments about men and women come to a fiery halt.

Lawrence's second point, drawn from the work of Simon Baron-Cohen, is that it's also silly to assume that men and women naturally all fall into their alleged types. Even if there are indeed typical male and typical female ways of approaching the world, these are still only averages that we take from a whole spectrum of behavior. That doesn't mean they aren't real, but we should appreciate that they're on a continuum, and that the two distributions of men and women take up a good amount of space, with room to overlap:

. . .Baron-Cohen presents evidence that males on average are biologically predisposed to systemise, to analyse, and to be more forgetful of others, while females on average are innately designed to empathise, to communicate, and to care for others. Males tend to think narrowly and obsess, while females think broadly, taking into account balancing arguments. Classifying individuals in general terms, he concludes that among men, about 60% have a male brain, 20% have a balanced brain, and 20% have a female brain. Women show the inverse figures, with some 60% having a female brain."

Lawrence goes on to summarize Baron-Cohen's theory that autism represents an extreme male brain, while noting that a sprinkling of mild autism-spectrum behavior probably does science (and society) some good:

It will not have escaped the notice of many scientists that some of their colleagues and maybe themselves have more than a hint of these "autistic" features. . .Indeed, we might acknowledge that a limited amount of autistic behaviour can be useful to researchers and to society-for example, a lifetime's concentration on a family of beetles with more than 100,000 species may seem weird, but we need several such people in the world for each family. And most of these specialists will be men. . .

It follows that if we search objectively for an obsessive knowledge, for a mastery of abstruse facts, or for mechanical understanding, we will select many more men than women. And if males on average are constitutionally better suited to be this kind of scientist, it seems silly to aim at strict gender parity.

However, in professions that rely on an ability to put oneself in another's place, at which women on average are far superior, we should expect and want a majority of women.

Still, he goes on to say that we would do well to find a place for each type in the other's favorite professions, since the fields are complex enough for some different sorts to be needed. In science, to pick one obvious example, people with better interpersonal skills would make better mentors for students and younger scientists. Too many potentially good careers are ruined by research advisors with no personal skills - well, no helpful ones, anyway. (I've known some who had amazing talents of enraging and antagonizing people).

And on top of all this, there's no evidence that creativity and original thinking, which are in perpetually short supply, have any male-brain female-brain bias at all. But as Lawrence points out, the techniques that we use to fill positions, in both industry and academia, are biased toward male-brain behavior: unshakeable self-confidence, quick recall of all sorts of data, self-promotion in the form of long publication lists, and so on. We would do better, he says, to give less weight to "salesmanship and pushiness".

I think he's got a good point. For example, it occurred to me fairly soon after coming to industry that most of the people who climbed the ladder in a company did so by devoting all their time to climbing the ladder. Anyone with a range of interests and activities, not all of them necessarily relevant to gaining power and position, was at a disadvantage and would generally lose out to the people who had made getting those things their life's work. Of course, in this way you end up promoting some people into supervisory positions whose main skills have nothing to do with being able to usefully supervise anyone, but that's a well-known problem, too.

Turning Lawrence's recommendation into something workable isn't going to be easy, though. Originality and creativity are famously hard to measure, or often even to recognize. Some people seem to have an eye for talent (I'm thinking of some historical examples from the arts world), but if it exists, it's a rare quality. And in many cases, we're going to be asking less creative people to evaluate more creative ones, which has been a traditional recipe for disaster.

Comments (14) + TrackBacks (0) | Category: Who Discovers and Why

March 8, 2006

How Not to Do It: Liquid Nitrogen Tanks

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Posted by Derek

N2%20tanks.jpgA colleague of mine forwarded a copy of an accident report from Texas A&M. It seems that in mid-January they had a bit of a blowout there, thanks to a big liquid nitrogen tank. Now, liquid nitrogen cylinders are normally fairly benign, as long as you don't freeze your external organs off with the stuff or leave the liquid sitting around where it can condense oxygen out of the air. But idiocy will find a way - note the regular cylinder on the right and the new, improved model next to it.

These guys are usually equipped with pressure relief fittings, since nitrogen does tend to want to be a gas, and gases do tend to want to expand quite a bit. This tank, though, which seems to have been kicking around since 1980, had been retrofitted by a real buckaroo. Both the pressure relief and rupture disks had failed for some reason in the past, so they'd been removed and sealed off with metal plugs. You may commence shivering now.

Why it didn't blow long ago is a real stumper, but presumably people were taking nitrogen out of it quickly enough to keep things together. Not this time, though: at around 3 AM, things came to a head as the internal tank (these things are double-walled) expanded until it pressed against the outer one. That kept it from expanding anywhere else except on the ends, and as fate would have it, the bottom blew out first. The engineer's best guess is that this took place at around a 1200 psi load. It must have been quite a sight, although it's a damn good thing that no one was around to see it. I'll let the engineer's report take it from here:

The cylinder had been standing at one end of a ~20' x 40' laboratory on the second floor of the chemistry building. It was on a tile covered 4-6" thick concrete floor, directly over a reinforced concrete beam. The explosion blew all of the tile off of the floor for a 5' radius around the tank turning the tile into quarter sized pieces of shrapnel that embedded themselves in the walls and doors of the lab. The blast cracked the floor but due to the presence of the supporting beam, which shattered, the floor held. Since the floor held the force of the explosion was directed upward and propelled the cylinder, sans bottom, through the concrete ceiling of the lab into the mechanical room above. It struck two 3 inch water mains and drove them and the electrical wiring above them into the concrete roof of the building, cracking it. The cylinder came to rest on the third floor leaving a neat 20" diameter hole in its wake. The entrance door and wall of the lab were blown out into the hallway, all of the remaining walls of the lab were blown 4-8" off of their foundations. All of the windows, save one that was open, were blown out into the courtyard.

No one seems to have heard the celebrations, but someone noticed that the building's water pressure had gone a little wimpy and went to investigate, which I'll bet was a real eye-opener. I get the impression that they're still trying to track down the Mr. Fix-It who inadvertently rigged the tank for takeoff. The company engineer who came in to investigate noted that he's seen these kinds of "repair" jobs before, generally after they've powered through something.

Comments (24) + TrackBacks (0) | Category: How Not to Do It

Things Turn Nasty

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Posted by Derek

Back in 2003, I wrote about the excitement over PYY3-36, a peptide which showed some profound effects on feeding in animal models, but I wasn't exactly jumping up and down:

. . .You're not going to be able to take this orally. It's going to be i.v. or bust for some time, I'm afraid. There's some hope for taking peptides of this size nasally, although it's tricky, and there's an outside chance of getting them through via a transdermal patch, but I wouldn't bet on that one. . .And these are early days. The obesity field is cluttered up with promising ideas that have deflated. . .

A small company called Nastech took a whack at the idea, using the nasal delivery route, and they had some promising Phase I data. Well, OK, Phase I isn't designed to show efficacy, but they looked anyway, and saw some. In the eleven patients who completed the study, that is. Well, OK, in the nine responders. But the data were interesting enough to get Merck on board to fund some real efficacy studies.

Well, the results are in, and the headline says it all: "Nastech Pharmaceutical Company Reacquires PYY3-36 Nasal Spray. . ." is how the press release starts, and you know what that means. The stuff missed its endpoints most powerfully, and Merck hit it back over the net. Makes you wonder what the deal was with the positive human data that had been reported by others back in happier days, doesn't it?

Nastech makes what they can out of the blood levels they observed, and says that they hope to take the peptide back into Phase II once they've worked out a better dosing regimen. I wouldn't stand on one leg while waiting for that happen, but I wish them luck. There may be other indicators over the next few weeks or months. As Fred Cohen points out, Amylin is also working on the same peptide with an injectable dosing protocol, and if you see them pulling out of the field then that's going to be that.

Perhaps the saddest paragraph in the Nastech release is this one:

Nastech intends to cooperate with Merck in the production of a manuscript to be submitted for publication concerning the clinical trials performed by Merck. Merck noted that the 'interaction between Merck and Nastech has been positive and professional', and that they 'would welcome the opportunity to collaborate with Nastech again should the appropriate opportunity arise.' Nastech as well would welcome the opportunity to work with Merck in the future.

I'll bet that they would, and I hope that they get the chance. For now, it looks like this work is going to go to where drug development projects go when they die: publication in a peer-reviewed scientific journal. For industrial scientists, that's a sad way for things to end. The obesity field may have yet another failed hypothesis to deal with; you'd think that it already had ruined enough for anyone.

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March 6, 2006

Man Hands on Misery to Man

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Posted by Derek

Some comments here called my attention to a piece by Philip Greenspun, "Women in Science". That's not the best title, because his points aren't so much about the position of women in science, but of everyone. And a pretty damned bleak position it is:

"Why does anyone think science is a good job?
The average trajectory for a successful scientist is the following:
1. age 18-22: paying high tuition fees at an undergraduate college
2. age 22-30: graduate school, possibly with a bit of work, living on a stipend of $1800 per month
3. age 30-35: working as a post-doc for $30,000 to $35,000 per year
4. age 36-43: professor at a good, but not great, university for $65,000 per year
5. age 44: with young children at home (if lucky), fired by the university ("denied tenure" is the more polite term for the folks that universities discard), begins searching for a job in a market where employers primarily wish to hire folks in their early 30s."

I note that this is an academic career path, for one thing, and I also note that even from that perspective it's not very accurate. Eight years in grad school? Five more as a post-doc? I'd have lost my mind long before the end of that. I know that the molecular biology people take longer than chemists, but I don't think even they take that long. As for me, I spent 4 1/2 years in grad school, and one year on a post-doc - all finished and in the work force at age 27. (Keep those figures in mind - later on he's going to tell us that I wasted my time and earnings potential).

Greenspun goes on to contrast his view of a science career with his take on some other professions. Someone with the same intelligence and drive to get hired into a tenure-track job at Berkeley, for example, would (according to him) likely be a top specialist as an MD by the age of 44. In business, at a company such as GE, this person would be "handed ever-larger divisions to operate, with ever-larger bonuses and stock options." As a lawyer, they'd be a half-million-dollar-per-year partner or "a professor at a law school supplementing her $200,000/year salary with some private work". Even public school teachers do better than scientists, he contends - by his calculations, they're making $50,000/year by the time they're thirty. I'll defer to others from those professions who can assess how realistic these comparisons are; I'll only say that I entertain grave doubts.

No, where I can speak up is in his description of my own job. His belief is that students only go into science because they have the examples of their own professors in front of them, and they don't have the foresight to ask anyone about what the profession is really like:

"Some scientists are like kids who never grow up. They love what they do, are excited by the possibilities of their research, and wear a big smile most days. Although these people are, by Boston standards, ridiculously poor and they will never be able to afford a house (within a one-hour drive of their job) or support a family, I don't feel sorry for them.

Unfortunately, this kind of child-like joy is not typical. The tenured Nobel Prize winners are pretty happy, but they are a small proportion of the total. The average scientist that I encounter expresses bitterness about (a) low pay, (b) not getting enough credit or references to his or her work, (c) not knowing where the next job is coming from, (d) not having enough money or job security to get married and/or have children. If these folks were experiencing day-to-day joy at their bench, I wouldn't expect them to hold onto so much bitterness and envy."

The average scientist he encounters is like this? Fun crowd he hangs with. I'm just imagining what a scientific meeting would be like if his statement reflected reality: hordes of shuffling, pissed-off scientists, hands jammed in the pockets of their threadbare trousers, scowling at each other as they joylessly trudge through the hallways. Off in the distance is a chortling Nobel Prize winner. . .

Of course, there's always the objection that I work in industry, far away from the salt mines of academia. And it's true, after a good close look at the academic world, I decided that it wasn't for me. But Greenspun has me covered in an appendix:

"For people with PhDs in Biology, there are a lot of jobs at pharmaceutical companies paying more than $100,000 per year. Considered on purely economic grounds, these jobs don't justify the time and foregone income invested in a PhD. There are 22-year-olds earning $150,000 per year selling home mortgages.

What about the working conditions? Surely it is more interesting to be a scientist at a drug company than to be selling home mortgages? It depends on the worker's personality. Are you introverted? Want a job where you seldom have to meet anyone new? Want to sit at the same desk or bench year after year and work mostly by yourself? Get most of your satisfaction from solving puzzles? Have we got the job for you: industrial scientist!"

Ah, that clears things up. Yes, despite his talk of pharmaceutical company jobs, it's obvious that Greenspun has not the faintest idea of what those jobs are really like. Just for the record, we work in groups, in teams, in departments over here. We have to talk to our colleagues and present our results constantly in front of rooms of people. The most successful folks in the industry are the ones with the skills to talk to, listen to, and deal with people from all the other science and business areas in the company. If you can't stand to meet or talk to anyone, your career is going to go nowhere.

My problem with Greenspun, after that otherworldly section on industry, is that I can't trust him in any of the other parts of his piece. (Can he find me one of those 22-year-olds earning 150K/year selling mortgages?) He's shown a willingness to just make stuff up and present it as fact - and you know what we scientists think about that. It's a pity, because he has a few good points to make. But despite his denials, they're buried in bitter fantasies.

Comments (37) + TrackBacks (1) | Category: How To Get a Pharma Job

March 5, 2006

Journal of Biological Chemical Biochemical Chemical Biology

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Posted by Derek

My inbox at work has been receiving promotions for the new American Chemical Society journal ACS Chemical Biology. I've looked it over, and it's the sort of thing that I like to read. I should also note that they've started a wiki on the whole topic of just what chemical biology is, and it'll be interesting to see if they get contributions.

But there are other e-mails demanding my attention. The Nature Publishing Group has been sending me notices about new journal, Nature Chemical Biology. That one's not bad, either. Watching them fight with the ACS journal over the exact same papers should be fun.

Of course, you wouldn't expect a powerhouse like Elsevier to stay out of this, but they can point out that they were already there: Chemistry and Biology has been around for years. I don't read it as often as I probably should, but it's published some interesting articles.

And if Elsevier is there, can Wiley be far behind? That would be the Euro-flavored ChemBioChem, awkwardly named but a pretty good read. They have a bit more of a drug-discovery angle to them than the Elsevier journal, to my eye, and they've also been around a few years.

That angle is supposedly going to be dealt with more explicitly by Chemical Biology and Drug Design. This is the journal formerly known as the Journal of Peptide Research, but the times, they have changed. Would you be interested in BioMedCentral's BMC Chemical Biology? If you have some time after that, the Royal Society of Chemistry has synthesized their Chemical Biology Virtual Journal by amalgamating relevant papers from their other publications. How about Current Opinion in Chemical Biology, in case you're having trouble getting a handle on what's going on?

What's going on, as is probably clear by now, is a major publishing pileup. But there's something to be learned from it. If the various publishers didn't think that there was a market (for submissions and for subscriptions) they wouldn't be so eager to get in on the action. In some coming posts, I'll be taking a look at just what action that is, and whether it represents a takeover of biology by chemistry or the reverse.

Comments (7) + TrackBacks (0) | Category: The Scientific Literature

March 2, 2006

Technical Difficulties

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Posted by Derek

Today's posts (on Matthias Rath and Procter and Gamble, respectively) disappeared well before noon due to a Movable Type problem back at Corante HQ. I think we should be back to normal soon, but wanted to leave this placeholder up for now. I'll leave those two up for Friday, and we'll get back on track next week. . .

Comments (0) + TrackBacks (0) | Category: Blog Housekeeping

Procter and Gamble Throws in the Towel

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Posted by Derek

As mentioned in a comment thread here several days ago, P&G looks to be finally giving up on in-house drug development. 300 jobs are being cut at the Mason, OH site, and they're all from Drug Discovery. That'll pretty much do it - all that's left now is drug development for inlicensed compounds.

If you check P&G's pharmaceutical web site, though, you won't be able to tell that anything is going on. Still, the front-page mentions of career opportunities in Marketing and Brand Management are perhaps a tip-off to the company's priorities. The R&D page is particularly painful:

We are rapidly expanding our capabilities and capacities. We have internal capabilities in most areas of pharmaceutical discovery, development and marketing. We also are committed to expanding these capabilities, gaining access to the latest scientific knowledge, utilizing the latest in technology advancements through active partnering with academia, national laboratories, and biotechnology and other pharmaceutical companies.

Sure thing! Procter and Gamble has been messing around in the drug discovery area for many years now, with painfully little to show for their own efforts. Despite some good people, some of whom have been subsequent colleagues of mine at other companies, they've never made that much headway. Eye-rolling comments about shampoo and fabric softener are not uncommon from former employees.

P&G has done all sorts of deals with smaller companies, and I presume the more advanced of these will continue on their (merry?) way. But in the long run, you have to wonder. Discovery research has turned out to be too foreign for the company to deal with. And while development is different, it's a lot more like drug discovery than it's like the laundry detergent game. Who's to say that it won't eventually drive the brand managers crazy as well?

Comments (15) + TrackBacks (0) | Category: Drug Industry History

March 1, 2006

Deception Begins at Home

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Posted by Derek

I recently had an opportunity to look into some self-described autism treatments on behalf of a friend. There are huge numbers of desperate and hopeful parents out there, and there are some desperate and hopeful people selling things to them, too. The stuff I looked at was not, as far as I could tell, a cold-hearted scam, and considering the things you find in such disease areas, that's saying something. I think that the person involved believes, and wants to believe, that he's doing good in the world, and I'm sure his customers want to believe the same things.

At the same time, unfortunately, I don' t think much good is being done, but I can't get as enraged about it as I can some other situations. Take vitamin fraudster Matthia Rath, for example. He has recently withdrawn his lawsuits against a number of people and organizations in South Africa, in a sudden and unexpected move. Among them are the Health-e News Service, the group that broke the story of how some of Rath's alleged anti-HIV success stories involved patients who were taking antiretroviral drugs the whole time. Also off the hook is Dr. Eric Goemare of Medicines sans Frontieres, sued for defamation after characterizing Rath as a liar and a killer (which descriptions I find perfectly fitting, myself).

Says Goemare: "We are pleased that this phenomenal waste of time has ended." Dr. Rath is, of course, an expert at wasting things: people's time, their money, their hopes, their lives. I'd extend that list to include the oxygen he consumes by continuing to walk among us, but perhaps that's just me.

Comments (3) + TrackBacks (0) | Category: Snake Oil