About this Author
College chemistry, 1983
The 2002 Model
After 10 years of blogging. . .
Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: email@example.com
December 29, 2005
Over at Asymmetrical Information, here's some interesting speculation on what would happen if someone actually developed an HIV vaccine that worked. Plus, bonus mix of Paul Krugman-bashing and grudging Krugman approval!
What's the difference between an inventor and a tinkerer? Any why don't more people realize that there is one? Thoughts on this, with reference to the Wright Brother's alarming aircraft engine and the man who built it, here. Bonus Jared Diamond-bashing!
Monitoring mosques and other buildings for radiation, are we? It's interesting that we need to get as close as we are. . .and are we actually pointing any instruments at these sites while we do it? Jay Manifold connects the dots, since the media are doing such a lousy job of it. Bonus two-cultures complaint included, in this link.
You don't see quite as much of it in chemistry, but here's a blast at accelerated publication policies in scientific journals.
+ TrackBacks (0) | Category: General Scientific News
December 27, 2005
A while back, I mentioned in passing that some chemical structures were ugly ones from a med-chem perspective. That prompted a reader to ask, very appropriately, what makes a structure ugly. The quick answer is easy, and a bit embarassing: an ugly drug structure is one that looks too different from other things that we already know are drugs.
Hah! There's the "Rule of Five" in a nutshell for you. But there's something to that approach, although I don't approve of it being used religiously. If a compound deviates wildly from the kinds of structures that we already know work, you do run some risks. Those deviations can be in sheer size (molecular weight), where we know from bitter experience that many synthetic compounds up in the high hundreds of daltons seem to have trouble being absorbed and transported around the body. Not all of them - but more and more as you go up.
Or you can deviate in things like the number of polar functional groups. Way too few of them, we also know, and your compound is so greasy that it also can have absorption problems, and the liver will tend to rip it to pieces even if it gets that far. Way too many polar groups, though, and the compounds seem to have problems getting through cell membranes. Again, these aren't written in stone, but your chances of success decrease the further away that you get and your research efforts should be planned with those odds in mind.
Beyond these parameters, there are specific chemical reasons to dislike a structure. If it has strongly reactive functional groups in it, there had better be a good reason for them. After all, there are a lot of things in the body to react with, almost all of which you'd want to avoid. Some chemotherapy agents fall into this category, which goes a long way toward explaining their low toxicity threshold. To give you an idea, a structure with an acid chloride in it will be dismissed out of hand, and an epoxide will be regarded as guilty until proven innocent.
Reactive groups can also include things that are chemically stable, but will fall apart under physiological conditions. Very acid-labile groups, for example, are probably not going to make it through the hydrochloric acid bath of the stomach (unless you coat the tablet to make it through into the intestine). And something like a simple methyl ester probably isn't going to survive, either, because there's an awful lot of acylase/hydrolase enzyme activity floating around in the intestines and in the blood. (You can use these effects to unmask your active drug once it's in the body - a "prodrug" - but that's another story).
And, finally, we reserve the right to call a structure ugly if it looks just plain too hard to make. After all, we generally have to make hundreds (sometimes thousands) of related analogs during the early development of a lead structure, and if the shortest route into the series is fifteen steps long, that's just not going to happen. The odds of success go down as the difficulty of the chemistry goes up, so all things considered, we'd rather work on something that we can deal with. There are plenty of compounds that are reasonable by all other criteria except this one, I'm sad to say, which means that we pay attention any time an interesting new synthetic method comes along. It might lead us into chemical spaces that no one's had a chance to explore (or claim!)
+ TrackBacks (0) | Category: Drug Development
December 23, 2005
As you may have noticed from the all-times-of-day posting schedule around here the last few days, I'm already on vacation. I'll return to the Wonder Drug Factory on January 3, and I'm already glad that I wrote myself my traditional note reminding me what I was doing and where things are. I'll continue to post here reasonably often until then, although there will be a missed day or two while my kids jump up and down on top of me. And I have to take time, naturally, to deal with questions such as the one just asked by my son, who wanted to know if anyone has taken one of those half-eaten cookies you find on Christmas morning and tried to "get some of Santa's DNA".
One of my first acts on returning to the lab will be to clean the place up a bit. I have detritus from two or three past projects scattered all over the place, and it doesn't need to be where it is. Some of it is going to go right into the red waste can, of course. Heck, some of it should have gone right in the red waste can right after it was made, but you don't have any way of knowing that at the time. But some of it will go to a (theoretically) more useful place.
In a chemistry research department, people are always making batches of intermediate compounds, often in reasonable amounts (5 to 100 grams, say). These are things that you can't buy from any supply house. Often they're based on chemical scaffolds that have already been shown to be useful in one or more projects, and have functional groups hanging off of them that are ready to be elaborated. This is valuable material, and you don't want to throw it away. What our department has done, like many others, is set up a catalog of these things and a central place to store them. I need to move a bunch of these home-made wonder drug building blocks out of my hood and down the hall, so that someone can possibly make use of them. And I could use the space - everyone comes out ahead.
That'll give me the elbow room to work on my current project, and to keep moving along (once again) on my side project, which I haven't spoken about much recently. Instrumental difficulties and other things have slowed it down, but it's most definitely still alive, and will (I hope) start off in several directions come January.
+ TrackBacks (0) | Category: Life in the Drug Labs
December 22, 2005
I was driving last night and listening to NPR, when they broadcast a commentary by Joe Loconte of the Heritage Foundation. This was bemoaning the Dover decision tossing Intelligent Design out of the local Pennsylvania school curriculum, and I'm afraid I ended up adding some loud and vulgar commentary of my own while hearing it.
Loconte's analogy was to the Big Bang theory in cosmology. He claimed that when the theory was proposed, that some of the objections to it were because of its similarities to the creation account in Genesis. I wasn't aware that the Big Bang was considered too religious, but it seems that this was the case for some physicists. That's quite an irony, though, considering some of the religious objections to it now. (Here's a rundown from everyone's favorite creationist web site, Answers In Genesis, certainly the first time I've ever linked to them. Hours of entertainment await you there, though, I have to admit.)
And you can see where the rest of the commentary went. We should make room for seemingly heretical theories in science, even if they seem to have religious overtones, because the orthodox dogma of the scientists can indeed be overthrown, yea verily, just as it was with the Big Bang theory. Loconte has sounded this note before, many times - see this CNN transcript where he goes on about the "high priests of evolution" and the "divergence of views within the scientific community" on the issue.
But Loconte neglected to mention that Big Bang cosmology won its case by providing empirical evidence, and plenty of it. And this was done completely within the framework of scientific discovery - making testable predictions, for one thing.
And that's where the analogy with ID breaks down. If Intelligent Design has made any testable predictions, I've missed them. If it's advancing due to further research, I've missed that, too. Loconte has made the error, which is unfortunately common in those with no scientific background, of assuming that ID is just another scientific theory because it claims to be. "I can't see how something this complicated could have happened except by God doing it" is not a basis for scientific discovery. For that, you want something like "I can't see how something this complicated could have happened. Let's look at all the evidence we can get and follow it no matter where it leads."
+ TrackBacks (0) | Category: Current Events | Intelligent Design
December 21, 2005
Regular readers might enjoy seeing some of the posts from this blog recapitulated in this New York Times story about this week's approval of a new cancer therapy from Bayer:
. . .Although every field has suffered, cancer has had the greatest chasm between hope and reality. One in 20 prospective cancer cures used in human tests reaches the market, the worst record of any medical category. Among those that gained approval in the last 20 years, fewer than one in five have been shown to extend lives, life extensions usually measured in weeks or months, not years. . .Drug companies have been promising for years that gene-hunting techniques would yield targeted nontoxic therapies that melt cancer, but few cancer medicines fit that profile. . ."There are all these myths having to do with cancer drugs," Dr. Steven Hirschfeld, an F.D.A. medical officer with expertise in cancer, said. "That they're very targeted, when in fact all these drugs have multiple targets. That they're nontoxic, when in fact the latest ones have their own set of side effects. And that they're cures, when they are not."
This new compound is the first in a wave of multiple-kinase inhibitors. It's going to be very interesting to see how these molecules work compared to the earlier wave of more targeted therapies. Good luck to everyone involved - the researchers, the companies, and most of all, to the patients.
+ TrackBacks (0) | Category: Cancer
December 20, 2005
The last time I touched on Intelligent Design around here, things were pretty lively, and I promised not to return to the topic until the Kitzmiller decision came down. Well, here it is (PDF).
Good luck getting that link to load today, though. I think that this one from the York Dispatch is working better. From what I've read so far, Judge Jones has completely hammered the ID case flat:
". . .The Board contacted no scientists or scientific organizations. The Board failed to consider the views of the District's school teachers. The Board relied solely on legal advice from two organizations with demonstrably religious, cultural, and legal missions, the Discovery Institute and TMLC. Moreover, Defendants' asserted secular purpose of improving science education is belied by the fact that most if not all of the Board members who voted in favor of the biology curriculum change conceded that they still do not know, nor have they ever known, precisely what ID is. To assert a secular purpose against this backdrop is ludicrous. . .Defendants have unceasingly attempted in vain to distance themselves from their own actions and statements, which culminated in repetitious, untruthful testimony. . .
. . .Those who disagree with our holding will likely mark it as the product of an activist judge. If so, they will have erred as this is manifestly not an activity Court. Rather this case came to us as the result of the activism of an ill-informed faction on a school board, aided by a national public interest law firm eager to find a constitutional test case on ID, who in combination drove the Board to adopt an imprudent and ultimately unconstitutional policy. The breathtaking inanity of the Board's decision is evident when considered against the factual backdrop which has now been fully revealed through this trial. The students, parents, and teachers of the Dover Area School District deserved better than to be dragged into this legal maelstrom, with its resulting utter waste of monetary and personal resources. . ."
+ TrackBacks (0) | Category: Current Events | Intelligent Design
I have a correspondent who's written me a few times about the Vioxx/Celebrex/NEJM situation, and I thought I'd pass along some of his thoughts. He's not buying my idea that the New England Journal is worried about being sued, for one thing. As he points out, the various liability battles that have taken place over the last twenty years also have had potential for that sort of thing, and no one's done it yet.
And as for Pfizer's big Celebrex trial, he regards it as four years worth of lawsuit insurance, and cheap at the price. That's a reasonable idea, unfortunately, but I wonder if that would slow down a sufficiently motivated member of the plaintiff's bar. After all, they could make the argument that the company clearly had no idea (italics theirs!) if their product posed a cardiovascular risk or not - that's why they had to run a trial, naturally - and meanwhile had recklessly exposed consumers to the dangers of this insufficiently tested drug. . .man, once you start on those italics, it's hard to stop.
However, my correspondent isn't even sure that this is an ethical trial at all. (That Forbes article I linked to the other day had quotes from others raising such concerns). If you believe that COX-2 inhibitors have mechanism-based cardiac risks (a hypothesis publicized best by Garrett Fitzgerald at Penn), then Celebrex isn't going to be able to escape. There's room to argue that the COX-2 drugs don't have as good a gastrointestinal safety profile as had been hoped, either, which would take away another reason for their existence (and another ethical rationale for the new trial). Celebrex had better be good at relieving pain. . .
I should point out that if these effects are real, neither of them are things that would have been obvious earlier in the development of the COX-2 drugs. The rationales for their development were actually quite compelling at the time (just ask the University of Rochester - anyone heard from them recently?) But that's drug development for you. Every single new drug has risks, many of which aren't even known until millions of people take them. Would that it were different, but it isn't.
+ TrackBacks (0) | Category: Cardiovascular Disease
December 17, 2005
I wasn't an eyewitness to this one, although I wish I had been. I pass it on secondhard from a former colleague of mine, on which it made an understandable impression.
Bromine's an odd element. The two lighter halogens leading up to it are nasty gases. Fluorine, the first one, is actually beyond merely nasty, being a hazard to life from several different directions. Chlorine is something you can handle,although it was still nice enough to be used on the battlefield in World War I. But bromine is the first one of the series that makes the grade as a liquid at room temperature and pressure.
All the halogens have colors - for example, I'm told that liquid fluorine is green, not that I hope to see any of the damned stuff, and liquid chlorine is supposed to be yellow. Iodine is notoriously purple, and For its part bromine is a deep, almost opaque red-orange. It's one of those liquids that hasn't forgotten its gaseous heritage, and you always see it with a red haze of vapor above it. It's unmistakeable.
You'd think. Our story begins, as do so many fine lab disaster tales, with the phrase "There was this summer student. . ." In this case, there was this summer student whose grad-student supervisor thought he was ready for a spot of bromine work. They'd ordered a fresh bottle, which had come in from Aldrich the day before, and everything was ready for a good old-fashioned bromination reaction. As the chemists here know well, if you add bromine to a compound with an exposed carbon-carbon double bond, it'll react with the alkene, breaking it down to a single bond with a bromine on each carbon. Sometimes it's fast enough that you can see the red color disappear as the stuff drops into the reaction, and you can just go until the color persists, but sometimes it hangs around as an orange solution for a while.
So, our grad student leaves for lunch, entrusting this small-scale bromination to his ready-to-solo summer undergrad. And he wanders back presently to check out the reaction, but there's something wrong. The flask has no color to it, for one thing. For another, there are chunks of floating crud whirling around in the clear solution, and that's not right, either. He turns to the summer student and asks him if that's the bromination.
"Sure is!" Hmmm. Did he, in fact, use. . .bromine in this reaction? Oh yes, indeed. The bromine that just came in? Absolutely! What's that stuff floating around in the flask? Well. . .the bromine, right? Show me this bromine, then, by all means. And the summer student goes over to the opened shipment and lifts out the vermiculite packing material that's in there to keep the bottle from breaking during shipment. Behold the bromine!
No, you cannot make anything foolproof. Fools are too tricky. Needless to say, anyone who can't tell the difference between bromine and box-filler is someone that you don't want within a hundred yards of a working research lab. My colleague had not recorded the reaction of the grad student to this revealing answer, but I'm sure it involved raised voices and plenty of adjectives.
+ TrackBacks (1) | Category: How Not to Do It
December 15, 2005
I mentioned the anti-science types in Europe the other day, and I should mention that I have some personal history with them. I did my post-doc in Germany, long enough ago that there were two countries by that name. (I came back to the US about two months before the Berlin Wall fell, and had been traveling in Eastern Europe while it was falling apart, but that's another story).
I was doing free radical chemistry at the Technische Hochschule Darmstadt (in one of the buildings shown here, lower center), when one morning I arrived to find fire trucks and ambulances all over the place. Three or four floors above our labs, someone had firebombed the place.
I went up and had a look. They did a pretty low-tech job of it, with a can of gasoline, an immersion heater, and an electrical timer, but they did an awful lot of damage to the labs up there. And why did these particular labs get the treatment? Because they were engaged in work with recombinant DNA, naturally.
A group calling itself the
Zorne Zornige Viren (Angry Viruses, or maybe Viruses of Rage) left a note claiming responsibility. I read a copy of the thing, which went on about the military-industrial complex seeking to extend its patriarchal hegemony over untrammeled Nature and the very essences of our beings, la la la. You can imagine how melodious that all sounds in German. They were (as far as I know) never heard from again, but their attitude lives on.
Just take a look at these figures. There's a huge gap between most of European public opinion and the US (and between Europe and many Asian countries as well). I remember seeing similar magazine and newspaper survey results when I lived there. No matter what, genetic engineering always got hammered.
You can speculate for many paragraphs about why this is so, and people have. A fear of eugenics, from the racial theories of the Nazis? A romanticized view of nature and the land, from people who have gradually paved over large parts of it? Worries about private entrepreneurs owning rights to genetic material and running amuck without the State being able to restrain them? Not all the reasons to be cautious are are prima facie wrong, nor are they confined to Europe. Somehoe, though, they've combined there into a solid mass.
It must make it difficult for biotech researchers in Germany and France, though, if people ask them what they do. No doubt they talk about developing new medical therapies or diagnostic tools rather than say "I mess around with DNA all day". Safer to speak of the outcomes than the tools.
+ TrackBacks (0) | Category: General Scientific News
December 14, 2005
Pfizer's going to pull out the stops and spend up to $100 million to try to show that their COX-2 drug Celebrex is worth it. And they're going right to the source: the Cleveland Clinic. The study will be run by Steve Nissen, and he's forbidding the investigators under him from accepting money from all sides: drug companies, securities firms, trial lawyers, the lot. Celebrex will be compared head-to-head in high-cardiac-risk arthritis patients versus naproxen and ibuprofen (no aspirin, because of the near-certainly of bleeding problems at the doses involved).
A disproportionate number of arthritis sufferers are in the higher-risk groups, so this would seem to be an appropriate patient population. They're going to need to round up 20,000 of them, though, which is going to take some time, and the whole study won't finish up until 2009, at the current best guess. (Celebrex doesn't come off patent until 2013, in case you're wondering). I hammer on Pfizer a lot around here, because I think they're too big to be effective as a company. But I have to say that this is one case where being humungous (and, for now, full of cash) is an asset. This is going to be a long a costly trial, and you can count the drug companies capable of funding it on one hand.
Merck's taking a few shots in the press today, since they'd said that a study like this basically couldn't be run. No one would do it unless they felt they had to, that's for sure. But the loss of Vioxx as a competitor may have made this study possible for Pfizer, in that it could allow them to earn back the expense more easily. Celebrex first has to show that it doesn't have the cardiac risks associated with Vioxx (which are tiny, but real). If it doesn't do that, it's dead. But if it makes it past that, and actually works better than the cheaper alternatives, Pfizer will own the market. They'd at worst dominate it over some other COX-2 stragglers like Novartis's Prexige, which I don't think has even been filed for US approval yet. Novartis is on that short list of companies that can afford this kind of clinical expense for a single trial, and they may have to consider doing a big head-to-head with Celebrex if they want to stay in the market. Smaller studies aren't going to cut it in the COX-2 area any more.
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials
December 13, 2005
Why did the New England Journal of Medicine come out with their "expression of concern" last Friday? The more I think about the situation, the more I'm coming to agree with a speculation that I first saw over at Medpundit.
Don't get me wrong: I think Merck had every intention of making their VIGOR data look as good as possible when the study was published. Companies do that, and they should be punished when they push things too far. But if these three MI cases that we're disputing really did occur after the cutoff date for the study, then Merck had every right to exclude them from the data. (They had to be reported to the FDA, though, which is exactly what happened when it came time for approval). So why is the journal so worked up?
I don't know if this was a deliberate attempt (as some have speculated) to affect the outcome of the first Federal Vioxx case (now declared a mistrial). I hope not. But what I do think is that it was an attempt to clear the NEJM as a target of future lawsuits. Look at the sequence of events: the journal discovers the editing discrepency four years ago, but does nothing. Vioxx goes to the FDA for approval, goes on the market, sells in huge amounts, is hit with concerns over cardiac safety, is withdrawn from the market and is the subject of FDA and Congressional hearings. During this whole time, the journal and its editors say. . .nothing. Merck is hit with hundreds, then thousands of lawsuits. The first case goes to trial, and Merck loses with a huge jury award. But they win the second one, as the weeks and months go on. And the New England Journal keeps quiet.
Then the first Federal case starts up, and the journal's editor is brought in to give a deposition. And now the editorial staff springs into action, rushing out an unprecedented comment on a paper from their own journal that manages to publish on a Friday afternoon. All of a sudden, somehow, things couldn't wait.
Could it be that the plaintiff's attorneys, while questioning Gregory Curfman, mentioned that there could be more targets for litigation than just Merck? You run a prestigious journal there. . .probably influenced a lot of physicians to prescribe Vioxx, eh? Didn't see anything odd in the cardiovascular data, you say? Why, that's nearly a tort right there. . . I don't like to think that this is what happened. But it's not impossible, either. The journal's actions look like those of an organization that fears the legal discovery process. And why would you fear that, unless you fear that you'll be sued?
+ TrackBacks (1) | Category: Cardiovascular Disease
Welcome to the latest iteration of Grand Rounds. On behalf of the greedy rapacious pharmaceutical industry, I'm glad to be hosting this week. Unfortunately for everyone, the research end of the G.R.P.I. is not immersed in the ceaseless flow of promotional swag that the medical community has come to know us for. So for you practitioners dropping by today, enjoy a rare chance to interact with the drug industry with no free samples, pens, calendars, or trips to Martinique. Never been there, myself. . . (gazing at ice-covered yard). . . OK! Where were we?
Via Red State Moron, here's a real clinical practice problem for everyone to take a crack at: what should be done for someone who's not just endangering herself? (I've worked in diabetes drug discovery, and those glucose readings definitely qualify). Unbounded Medicine has an unusual clinical case for you to unravel as well. (Hoofbeats! I heard 'em!) And Intueri has a disturbing series of encounters with a psychotic patient.
Over at DB's Medical Rants, there's been a series of posts on "doctoring" - dealing with the different kinds of patients and understanding what they are (or may not) be trying to tell you. Here's the latest installment. Barbados Butterfly works (gently) with a very small patient indeed, and at Mr. Hassle's Long Underpants, a patient who's been through a lot worse provokes some thoughts (note the new domain name there, too!)
On the other hand, last week's host (Dr. Charles) has a handy guide which will allow any bozo from out in the parking lot to see a few patients and get away with it. Hey, I wear a white coat myself at work, and with this beard I'm pretty sure I could carry it off, especially for his offered $10 per head.
Working in the drug-discovery end of pharma, I don't deal with the clinical trials part of the industry too often. (Not nearly as often as I'd like is a better way to put it, I guess). But Amy Tenderich at Diabetes Mine has been invited to join a trial of a new inhaled insulin, and is weighing the offer. (Hey, at least we know what insulin does, as opposed to some other pharmaceutical brainstorms I've been involved with). Also on the receiving end of medical care, Oasis of Sanity experiences physical therapy as a therapee.
We live in an odd country, both in terms of the rest of the world and (especially) in terms of the human historical record. "Too much to eat" hasn't been a big problem for much of the species until very, very recently. So, asks Jon Schnaars at Treatment Online, if children are indeed getting too much high-calorie food, whose fault is it? The people who make them, or the people who feed it to them? And Insureblog points out that the consequences are financial as well as medical.
Matthew Holt of the Health Care Blog is now writing a weekly column for a site called Spot-On, and here he brings its readers up to speed on how health insurance in the US ended up the way it is. Meanwhile, Fixin' Healthcare wonders about the transition from a system that treats illness to one that prevents it. As for the system we already have, Healthy Policy runs into someone who doesn't seem to have a clue about just what that system is and what it means, and Sound Practice has a warning about coming changes in Medicare reimbursement costs. As A Chance to Cut. . . points out, though, it could always be worse - much worse. A roundup of the week's news in the hospital business is here at Hospital Impact.
Now, for some technology. Niels Olson is helping some MIT folks build a web forum for Tulane's medical school, and would appreciate some input. Tim Gee at Medical Connectivity looks at the decision on when to buy the fancy new medical device, and when to delay. Sounds like the same problem most tech-driven fields are having. Early adopters have their own problems, though: Dr. Andy has a really disturbing account of a hospital's experience with a new CPOE (computerized physician order entry) system. But if you want to see progress, take a look at HealthyConcerns and this piece about the latest outpatient facelift technology. Yikes.
Other medical news items this week are not quite as er, revolutionary as that last one, fortunately. Kidneynotes has the word on the latest CPR guidelines. Sumer's Radiology Site points out a recent publication on virtual bronchoscopy. As someone who could only be on the receiving end of all these flexible fiber-optic probes, allow me to cheer such techniques on. The Clinical Cases blog has a roundup (with links) of the recent news that Beethoven seems to have suffered from lead poisoning. It's not a metal that comes up a whole lot in drug research, I can tell you, and I promise everyone that I'll do my best to keep it that way.
Many patients need kidney transplants - but where, exactly, are we to find all those kidneys to be transplanted? Interested Participant has some thoughts. DocSurg has a look at a study on the safety of recycling unused polypropylene mesh in hernia procedures, which could come in particularly handy in countries that can't afford to throw the stuff out. In just some of those places, notes Aetiology, there's a strange epidemic of psychotic symptoms - an infectious disease, or not?
Chiisai Tokoro has a piece on the recent peanut allergy death by kissing. Count me with those people who've wondered why we never used to hear about this sort of thing. My guess is that (in places like the US) other sudden causes of death have decreased enough over the last hundred years, and we're finally noticing the low-probability ones. Dr. Emer has a look at one of those (fortunately) decreasing causes: what really happens during stroke. The Health Business Blog has a look at celiac disease, which seems to be something you hear about a lot more in recent years.
Of course, reading my site regularly and linking back to it is always recommended (let go of that keyboard it's - aarrgh!) Ahem. Jim Hu at Blogs For Industry noticed a piece I'd done on odd fungi and the like that are able to live in laboratory solutions that you'd swear were hostile to life, so he saw me and raised me: distilled water. We're not the dominant life form on the planet, y'know. Of course, the news would look a little different if it were covered from the dominant life form's perspective - Dr. Tony provides the latest bulletin.
The Christine Maggiore HIV case made clear how many people think (for no particular reason) that they know something about pathology. Trent McBride at Catallarchy actually does, though, and found a recent news treatment of the case that actually shed some light on the subject. Orac of Respectful Insolence has been covering this case as well. As it turns out, he was watching the same show, and has some penetrating comments on it, too. And Medpundit has a look at the first new medicine for gout in decades, and wonders if it's been worth the wait or not. (Now there's a disease indication I've never worked on. . .) Doc Around the Clock has a link to a recent video (Consumers Union, I think?) that whacks my industry over the head, but in a pretty funny way. Hey, at least there's not a cartoon version of Marcia Angell in there.
Prospective immunology is one of those well-worked-out sciences, rather like organic chemistry on its better days, so Gruntdoc looks at how well this year's flu vaccine matches up with the real antigen profile. Sticking with molecular biology (as a pharma researcher, I have little choice; those people have us hostage, y'know) Genetics and Health has a look at the recent sequencing of the dog genome, and what it could mean. We're keeping an eye on that over here, too, since dogs are one of our key toxicology models - never forget, "drugs kill dogs and dogs kill drugs". The Biotech Weblog has a piece on a recent genetic linkage to Alzheimer's Disease, which is an area that can use all the help it can get (says someone who tried for seven years to develop drugs for it).
Emergiblog has some requests - polite ones, really! - for how to work with the nurses in the ER. And Ian Miller has a mood piece set outside a rainy Australian emergency room.
And finally, now that I've helped to demonstrate just how many active med-blogs are out there, there's a call for a basic ethical code for health and medicine bloggers at the Medical Blog Network, and the recent NIH questionnaire is answered. (I didn't get one of those, come to think of it).
Well, that wasn't so bad now, was it? I appreciate the volume of submissions that came in this time, and I'll be glad to host another Grand Rounds
when Satan throws snowballs real soon now. Actually, this was fun to do, and I'm glad that we mere PhDs get a crack at it. Thanks to everyone who took the time to contribute, and remember to send links to Medpundit for the next edition.
+ TrackBacks (6) | Category:
December 12, 2005
The submissions for tomorrow's Grand Rounds continue to come in, and my wife continues to try to throw me off by referring to it as "Ground Rounds". While working on that, whatever I end up headlining it, I can recommend reading the recent series of posts from Chad Orzel over at Uncertain Principles. Under the heading of "A Week in the Lab", he's going into the details of his research project in atomic spectroscopy. "Slow-Motion Experimental Physics Live-Blogging"!
Update: I originally had a link to one of the series here, but Chad has assembled the whole series of posts in one handy spot.
I assume that he'll eventually get things working, but he probably assumes that, too. That doesn't make the lab work any easier. Although this is very far indeed from the kind of work that I do, the rhythms of research are the same. Fix three things before you do the one thing you were trying to - it's a universal law.
+ TrackBacks (0) | Category: General Scientific News
December 9, 2005
You don't see many articles in the medical literature titled "Expression of Concern". But that's how yesterday's release from the New England Journal of Medicine starts out (PDF).
The editors are expressing their concern over the published VIGOR trial data from 2000. It turns out that some time ago, the journal's editors had found a disk which had been part of the submission of the paper, and it contained earlier versions of the manscript. These had a blank table for cardiovascular events, and in what looks like another example of the wonders of the "track editing changes" function, it appeared that the table had been deleted by Merck two days before the final version. The journal wasn't sure what to make of this, and kept quiet (for four years) until their editor, Dr. Gregory Curfman, went through a deposition during this latest trial. He then saw a complete version of the earlier manuscript, which seemed to show more adverse cardiovascular data than appears in the final published version. (Forbes is all over this story; check that link for the full details).
This comes after the jury in the first Federal Vioxx trial had started deliberations. (For updates on how that's been going up until now, take a look at some of the Merck entries on Point of Law). What's it going to mean? Well, I would assume that the jury can't hear about this, for one thing, since none of this was introduced in testimony during the trial. It would seem to be fodder for a mistrial motion, though, if the verdict doesn't go the plaintiff's way. Should it be?
I've gone both ways on that question in the last few hours, but now I don't think so. While this story makes Merck look bad, idiotically bad, on closer inspection there isn't as much here as you'd think. The data in question are three heart attacks in the final weeks of the VIGOR trial. But the adverse cardiovascular event data in the paper, as published, didn't reach statistical significance, and they don't seem to reach it with these added in, either. On top of that, these data were submitted to the FDA during the drug's approval process, and (according to Point of Law) are on the Vioxx package insert itself.
So Merck might be guilty of making their data look better for the New England Journal of Medicine, but they're not guilty of hiding it from the world. And I'm not sure about that first charge, either. The lead author on the VIGOR study, Claire Bombadier of Toronto, told Forbes that the paper accurately disclosed the data and the she and the other authors are working on a response to the journal. But the headlines today are going to be variations on the theme of "Merck Hides Data". But as far as I can tell, they should be "Merck Looks Like Gang of Idiots, Blasts Away At Own Foot For Fourteenth Time". But that's not a crime. Yet.
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December 7, 2005
I can recommend this grim but well done article from last weekend's New York Times magazine. It's on the death from cancer of the author and critic Susan Sontag, written by her son.
He spent a lot of time with physicians and researchers during her last illness, and it wasn't time wasted. The article is a very good summary of the current state of the art in cancer research, and doesn't try to paper over the disagreements abpit how far along we are:
". . .advances in cancer treatment and, indeed, in the fundamental understanding of how cancer works have come far more slowly than many people expected. Periodically since 1971, when President Nixon declared his war on cancer, the sense that the corner is about to be turned takes hold. We appear to be in such a moment today. The National Cancer Institute has recently put forward ambitious benchmarks for progress in cancer research and treatment. As its director, Dr. Andrew von Eschenbach, a respected surgeon and a cancer survivor himself (he is also acting head of the Food and Drug Administration), put it recently: "The caterpillar is about to turn into a butterfly. I have never known more enthusiasm among cancer researchers. It's a pivotal moment." The suffering of cancer, he argued, will be well on its way to being alleviated by 2015.
The media have mostly echoed this optimism. It is not unusual to read about the latest "breakthrough" in cancer treatment, both in terms of understanding the basic biological processes involved and with regard to innovative new drug therapies. . . "
Exactly so, and that's one of the things that worries me. I know that it's in the interest of academic and industrial researchers to say that they're making great progress, but let's face it: great progress isn't being made all the time, everywhere, by everyone. You wouldn't know it to look at the press releases, though. It upsets me to see the words "cure" and "breakthrough" thrown around by both scientists and journalists who should really know better. It's understandable that such words should come to be devalued eventually, but we don't have to help devalue them as quickly as possible, do we?
David Sontag quotes Harold Varmus at Sloan-Kettering with some reasonably optimistic statements, but then says:
"Other research scientists seemed far more pessimistic when I spoke with them. Dr. Lee Hartwell, also a Nobel laureate, is president and director of the Hutchinson Center. He has urged that the focus in cancer treatment shift from drug development to the new disciplines of genomics and, above all, proteomics, the study of human proteins. Though he acknowledged the profound advances in knowledge made over the past two decades, Hartwell emphasized a different question: "How well are we applying our knowledge to the problem? The therapy side of things has been a pretty weak story. There have been advances: we cure most childhood leukemias with chemotherapy, for one thing. But the progress has been surprisingly weak given the huge expenditures that we've made. We're spending over $25 billion a year improving cancer outcomes, if you include the spending of the pharmaceutical companies. So you've got to ask yourself whether this is the right approach."
. . .Some researchers are even more skeptical. Mark Greene, the John Eckman professor of medical science at the University of Pennsylvania and the scientist whose lab did much of the fundamental work on Herceptin, the first important new type of drug specifically designed to target the proteins in the genes that cause cells to become malignant, agrees with Hartwell. The best way to deal with cancer, he told me, is to "treat early, because basic understanding of advanced cancer is almost nonexistent, and people with advanced cancer do little better now than they did 20 years ago."
I come down more on this side of things, myself. When we talk about the progress that we've made against cancer, we're almost always talking about the amount of knowledge we've accumulated. Measuring progress by how well we keep people from dying of the disease is more sobering, because the rate of exchange between those two currencies is rather poor. And we should keep in mind that much of the improvement in those numbers is due to early detection, often coupled with surgery. We need to do better.
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December 6, 2005
Nicholas Kristof had a column today (available on one of those private, subscription-only web sites here) with the title "The Hubris of the Humanities". It's a C.P. Snow-style "Two Cultures" lament, but at least it's one from the non-science side of the gap:
"In the U.S. and most of the Western world, it's considered barbaric in educated circles to be unfamiliar with Plato or Monet or Dickens, but quite natural to be oblivious of quarks and chi-squares. A century ago, Einstein published his first paper on relativity - making 1905 as important a milestone for world history as 1066 or 1789 - but relativity has yet to filter into the consciousness of otherwise educated people."
As someone who couldn't decide for a while between a humanities major and a science one as an undergraduate, I have to agree. I finally decided that it was going to be a lot easier to have a library in my basement than a lab. It also dawned on me, slowly, that many English majors had an entirely different approach to literature than I did, and that I wouldn't be very happy over there at all. And while graduate school in chemistry was often unpleasant, graduate school in English would have finished me off for sure.
I recall one day in my junior-year biochemistry class, with the professor telling us that we would be expected to have the whole citric acid pathway memorized for the test on Monday (great lamentation). Then I went straight to my Southern Literature class, where the professor came down hard on us by reminding us that we had to have finished the required William Faulkner reading by Monday, too. Groans from the English majors ensued, but I felt like yelling at them. "Look, you dolts", I wanted to say, "people read Faulkner for fun. No one memorizes the citric acid cycle because they enjoy it!" Of course, that's a major reason why many more people are familiar with Faulkner, isn't it? But not everyone likes "As I Lay Dying" (I do!), and not all parts of a science education have to be tedious.
This is a fundamental problem that my industry has. We're capable of making our own bad PR, of course, but even under blameless conditions we're doing something that most people don't understand very well and didn't enjoy having to try. So when we tell them it's hard, they think "Well, sure, of course it's hard. Tell me something I didn't know." And when we try to explain why there isn't a cure yet for (your least favorite disease here), it's hard to do so in terms that someone without a science background can really appreciate.
And that's one reason why the more irritating conspiracy theories still circulate. You know, the ones about how we pharma types really do have cures but we just aren't selling them (yet). Or how we caused those diseases in the first place, just so we could sell more drugs - I always take that one really well. Or how there are simple, cheap, safe herbal remedies for just about everything, only we Evil Pharma Overlords won't let them on the market. And so on, and so on. I've been arguing recently by e-mail with one of the "drug companies do nothing but rip off NIH" crowd, and it isn't easy. The guy has no idea of what he's talking about, or what I'm talking about, and it would take a fair amount of (unwanted) education to convince him.
But that's one of the things I try to do here - no, not convince idiots, I mean provide some education for those who might be interested. I think that the broad concepts of drug discovery (or pretty much any scientific field) can be understood by any reasonably intelligent person. They have to be explained the right way, of course, because the sad corollary to that statement is that there is no field of knowledge that can't be rendered incomprhensible. And still, even if it's done well, there are gaps. If someone lacks experience in research, there are things that have to be taken on trust.
For example: no, we don't have a machine that'll immediately print out the structure of any unknown compound you stick into it, no matter that such a device makes occasional appearances in movies and on TV. There are a lot of good reasons why that gizmo isn't available yet, and I could probably explain most of them to an interested lay party, given enough time. (For that, you could also read "given enough blog posts".) But in explaining drug discovery as a whole, it's easier to stipulate (in this case) that some time and effort has to go into make sure that the compounds you're looking at are really the ones you think you're looking at. Keep in mind that we scientists have to do the same thing if we're talking with someone in a scientific field that we don't know much about.
So, what to do? Science isn't getting any less important. I really don't think anyone can be considered well-educated without a grasp of the basic concepts of physics, chemistry, and biology. It's not as painful as it might sound. I appreciate the way that Arts and Letters Daily works in some links to science-overview articles - that kind of thing is bound to help. I wish that attitude were more widely shared, and I'm glad that Kristof made his point where he did.
Postscript: I should mention that Kristof goes on to talk about the consequences of scientific ignorance, but he makes the kind of mistake one makes after being marinated in the New York Timesfor years:
"It's true that antagonism to science seems peculiarly American. The European right, for example, frets about taxes and immigration, but not about evolution."
Which is a bizarre thing to say, on several levels. For one thing, hostility to science doesn't come merely from "the right". I'd say that science is equally admired (or used as a whipping boy) by both sides of the political spectrum. And if Kristof thinks that the Europeans can't be scared of scientific innovations, he must have somehow missed the long, loud upheavals about genetically engineered organisms and food over there. The European public cedes second place to no one in their fear of engineered food, and they don't mind going completely past any rational arguments to maintain their lead.
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The medical-blog roundup known as Grand Rounds is up today at Dr. Charles, with a wide selection of good reading.
And this is a good time to announce that I'm going to be hosting the next installment a week from now. Please feel free to send along links to any good blog posts on medical topics - your own, or ones you've come across when you're supposed to be working.
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December 5, 2005
Chemistry labs aren't known for the diversity of life forms - other than chemists - that inhabit them. It's true that I used to see the occasional mouse run across in an old building I worked in, and no, it was a little grey wild-type, not an escaped C57 Black from downstairs.
Now, once you get over to the desk areas, the usual array of plants do just fine. I have a paphilopedilum orchid that's come into bloom (looking very much like this), six or eight other orchids that are all doing fine, and a bougainvillea that's just finished a bloom cycle. In the spring I start a trellis on the sunny wall - last year I had morning glories blooming all over the place in here, and suggestions are welcome for the next crop.
So it's not like the atmosphere in the lab is toxid, although I wouldn't move the orchids into the fume hood, most likely. It's just not a place with a lot of natural habitats. But habitats are where you find them, as I realized when I saw a bottle of phosphate buffer cloud up on me the other day. (That's a well-known problem to real biologists and other power users; only a hack like me would leave phosphate buffer sitting around on the bench for weeks).
But phosphate I can believe as a growth medium. How do I explain some of the other things that show up? For example, I think there's something growing in a plastic bottle of saturated ammonium chloride down the bench from me, which would be impressive. My wife once saw something gaining a foothold in some saturated brine, presumably some halophilic organism escaped from the Dead Sea.
And my most alarming case, seen at a previous job in New Jersey, was a large, dark, fluffy ball of fungus floating in a bottle of saturated sodium bicarbonate. This stuff wasn't just hanging on in there, it was enjoying itself and reaching for more. There were two or three inches of solid bicarb on the bottom of the solution; it probably couldn't wait to get down and hit the mother lode. "That's a Jersey mold!" exclaimed a labmate.
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December 4, 2005
I mentioned phosphatase inhibitors while talking about okadaic acid the other day, and that brings me to a paper from the journal ChemBioChem (6, 1749) that I was recently reading. It's a collaboration from six German academic groups, led by one at the Max Planck Institute for Molecular Physiology in Dortmund. And there are some things about it that just don't seem to make much sense.
On the surface, everything's fine. They're investigating some cyclic peptide derviatives called stevastelins, which are microbial natural products known to show some phosphatase inhibitor activity. They produced some synthetic analogs of the natural products and ran them against several phosphatases of interest. They then turned around and did the same thing with some analogs of two more phosphatase-inhibiting natural products, roseophilin and prodigiosin. (For those of you who've done some bacteriology, that first compound is responsible for the red color of Serratia marcesens colonies).
Then the paper makes a sharp turn, as they move on to a 20,000 compound library that's been assembled by a German academic team. They screened this against their panel of phosphatase enzymes, and came up with 8 or 10 pyrrolobenzoic acid structures that showed some inhibitory activity. End of paper.
Well, the way I've presented this, it sounds like a fairly reasonable paper, if a bit of a hodgepodge. But it's the way everything's presented that makes me wonder. For example, their first group of stevastelin analogs is (for the most part) inactive against the five phosphatases they assayed. One of them hits the Cdc25a enzyme, one of them hits PTP1B, and one of them is active against MptpA, all of which are legitimate drug targets. But these compounds are all around 10 to 15 micromolar, which potency doesn't exactly make me leap up out of my chair.
But the authors refer to this as "pronounced selectivity for individual phosphatases". If you read the fine print, the "not active" values are compounds that were 30 micromolar and worse, so we could easily be looking at just two- or three-fold selectivity here. That is not my definition of "pronounced". Add that to the very weak potency, and you have results that I would toss if I saw them come out of a screening run. As a medicinal chemist, I'd start to get really interested at about a hundred times the potency of these compounds, and I'd be willing to bet that by that time the selectivity, if it's really there, would be long gone.
Their other natural product analogs are similar - one's as good as 3 micromolar against PTP1B, but others start to hit the 30 micromolar ceiling of the assay again. Even the active compound has a very unappealing chemical structure, which would only be developed by a desperate drug company indeed. (I particularly enjoy one of them that's reported against MptpA as "28.7 +/- 9.7" micromolar).
What's also irritating is the statement the authors make to justify all this: "We have previously forwarded the notion that biologically active natural products should be regarded as evolutionarily selected and biologically prevalidated starting points for inhibitor development." I'm glad they brought that up, since drug development from natural products has only been a popular technique for a century or so. The problem, as they're demonstrating here, is that if these compounds really are evolutionarily selected as phosphatase inhibitors, and the last hundred million years have only given you micromolar potency, then the odds of being able to push that lower by making half a dozen analogs are rather slim.
And that brings us to their screening efforts. Their compound library is "selected due to their diverse representation of reportedly bioactive scaffold elements". But 20,000 small molecules, however carefully selected, is not a very large collection. And when you get down to it, our compound collections in the drug industry are also supposed to represent a lot of reportedly bioactive scaffolds, and most of them are a couple of orders of magnitude larger.
The compounds from the screen are all micromolar. One of them looks a bit interesting, and possibly selective between the two kinases they ran it against. (What happened to the other enzymes by this point in the paper, I wonder?) I wouldn't want to try to develop these guys, but with the application of a lot of time, money, and effort, you might be able to get somewhere. Or you might wipe out within six months, which is how a lot of projects go, even the ones with better starting points than this, which is most of them.
Ah, but the authors are more optimistic than I am, because (I suspect) they haven't actually tried to do any drug development. "Further application of medicinal chemistry methodologies should allow for the development of more potent inhibitors for subsequent biological investigations in iterative cycles", they say. Oh, yes. Shouldn't it always?
Why am I going on at this length? Because I think that this paper illustrates a general problem: many academic labs do not understand what drug discovery entails, and (worse) they don't realize that they don't understand. The attitude shown here - presenting a few micromolar compounds as fine lead compounds and saying that med-chem should be able to sort things out - would actually be a good way to get fired at most companies. If this paper's data were somehow presented to me as a rationale for starting a project, I would create a distraction and dive for the door. No, there's still a long way to go.
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December 2, 2005
I missed this last night, but Pfizer finally fired Peter Rost. (I've spoken about him and his situation at Pfizer here and here).
He was hanging on in (well-paid) limbo due to a whistleblower suit he was involved in. The government declined to take part in the case this week, and the complaint was unsealed by a Federal judge. Pfizer's filed a motion to dismiss the whole thing, which seems likely to succeed, and they lost no time dismissing Rost. He can be classified as a long-delayed layoff from the Pharmacia merger. Among other things.
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December 1, 2005
Many people might not have noticed Rigel Pharmaceuticals until their stock fell down the stairs today. We'll pause a moment to consider the fate of this upbeat analyst, whose clients were long-and-wrong if they followed his recommendation to buy the stock a couple of weeks back. (There's a case to be made for buying the stock now that it's been hammered, but that's a topic for another day).
Rigel had taken an inhibitor (R112) of a kinase enzyme called Syk into the clinic for nasal allergies, and they missed their endpoints by a mile. They ran about 400 patients through a seven-day course of either their inhaled drug, a placebo, or Beconase, an inhaled steroid from GSK. Beconase was significant against placebo, but R112 wasn't.
But what must have been especially hard to take was that they'd already run an earlier trial with over 300 patients, where R112 seemed to work pretty well versus placebo. These results were a big part of why Rigel's stock was as high as it was. What went wrong?
We can start with the clinical trials themselves. I'm going to stipulate that today's result was correct, and that the compound did indeed fail. I think the two trials were measuring similar endpoints, so one possibility is that the earlier one was just run incompetently. I'm not in a position to say, and you'd like to rule that explanation out, but it's a possibility. What looks like a good P value can cover a multitude of sins.
A second level of explanation is the drug's mechanism. It's hard to believe that the underlying biology is completely mistaken, though. Syk is a reasonable target for allergy. It's involved in the signaling inside mast cells (and some other members of the immune system) after they're stimulated by an antigen, and blocking it would seem to be just the ticket.
I'm going to go with a hybrid theory. The first efficacy trial was only a two-day evaluation. Perhaps there's a compensatory mechanism that kicks in and cancels out the effect of the drug on repeated dosing? That would make this failure a team effort between the biology and the design of the first trial, and that's what seems most likely to me in the absence of other data. Fortunately for Rigel, this wasn't a particularly long or expensive trial - they announced only back in August that they'd enrolled their first patients. It's a nasty failure, but they got out of it relatively cheaply.
And they have deals with a range of other companies for other kinase inhibitor projects. One of them, though, is of particular interest after today's news. Pfizer is a partner of theirs for their next-generation Syk kinase inhibitors, this time aimed at the asthma market. Is my compensatory mechanism guess correct, and does it apply to that therapeutic area, too? Pfizer will be paying to find out. . .
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