Corante

About this Author
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

Chemistry and Drug Data: Drugbank
Emolecules
ChemSpider
Chempedia Lab
Synthetic Pages
Organic Chemistry Portal
PubChem
Not Voodoo
DailyMed
Druglib
Clinicaltrials.gov

Chemistry and Pharma Blogs:
Org Prep Daily
The Haystack
Kilomentor
A New Merck, Reviewed
Liberal Arts Chemistry
Electron Pusher
All Things Metathesis
C&E News Blogs
Chemiotics II
Chemical Space
Noel O'Blog
In Vivo Blog
Terra Sigilatta
BBSRC/Douglas Kell
ChemBark
Realizations in Biostatistics
Chemjobber
Pharmalot
ChemSpider Blog
Pharmagossip
Med-Chemist
Organic Chem - Education & Industry
Pharma Strategy Blog
No Name No Slogan
Practical Fragments
SimBioSys
The Curious Wavefunction
Natural Product Man
Fragment Literature
Chemistry World Blog
Synthetic Nature
Chemistry Blog
Synthesizing Ideas
Business|Bytes|Genes|Molecules
Eye on FDA
Chemical Forums
Depth-First
Symyx Blog
Sceptical Chymist
Lamentations on Chemistry
Computational Organic Chemistry
Mining Drugs
Henry Rzepa


Science Blogs and News:
Bad Science
The Loom
Uncertain Principles
Fierce Biotech
Blogs for Industry
Omics! Omics!
Young Female Scientist
Notional Slurry
Nobel Intent
SciTech Daily
Science Blog
FuturePundit
Aetiology
Gene Expression (I)
Gene Expression (II)
Sciencebase
Pharyngula
Adventures in Ethics and Science
Transterrestrial Musings
Slashdot Science
Cosmic Variance
Biology News Net


Medical Blogs
DB's Medical Rants
Science-Based Medicine
GruntDoc
Respectful Insolence
Diabetes Mine


Economics and Business
Marginal Revolution
The Volokh Conspiracy
Knowledge Problem


Politics / Current Events
Virginia Postrel
Instapundit
Belmont Club
Mickey Kaus


Belles Lettres
Uncouth Reflections
Arts and Letters Daily

In the Pipeline

Monthly Archives

February 27, 2002

More Imclone, More Food for Thought

Email This Entry

Posted by Derek

As you've no doubt heard, Imclone issued a press release this morning about their FDA meeting. It seems that if they can come up with more clinical data from Merck KGaA's European trials, along with clarifying some of their own numbers, then the FDA has agreed to look at a resubmission. Bristol Meyers-Squibb has been notable for their complete silence so far, which doesn't make them look very enthusiastic.

And as you've no doubt calculated, my short sale of Imclone's stock yesterday did not turn out to be very lucrative. Nor will it be, most likely. But I'm keeping the position for now, looking to escape fairly soon without too much financial damage. This FDA news, while not the worst that could have happened for the drug's development, isn't all that good, either.

The European data won't be available until the end of the year, even if all goes well. That trial is still in the enrollment phase, and it looks like Germany's Merck is being very careful about which patients go in (caution made even more important by the FDA's reaction to Imclone's data.)

That brings the drug to market a year late - again, if everything works like it's supposed to. That's bad news for the cancer patient population, because the patients who would benefit most immediately from the drug may not be around in another year to take it. And it's bad news for Imclone and BMS, too, because competing therapies aimed at the same molecular target (the epidermal growth factor receptor) are coming along. Some of these aren't antibodies, like Imclone's candidate - they're small drug molecules. If those work, they'll be easier and cheaper to produce in quantity. If they don't set off too many side effects, they could be real competition.

Who to blame for all this? The Wall St. Journal weighs in with another Imclone editorial (no free link,) as they did back on Feb. 13th. I'd been kicking around the idea of commenting that one out paragraph by paragraph, and now I'm already behind.

They came down hard on the FDA both times, suggesting that the government changed the requirements in mid-stream, and that the efficacy standards are too stringent. As odd as it feels for a pharma researcher, I have to come to the FDA's defense here. It was Imclone's (and, let's not forget, BMS's) responsibility to make sure that the clinical data were ready for approval. Arguing about what the FDA should be is beside the point: every drug company knows what the FDA is.

And every large drug company knows what sorts of submissions have a more solid chance of being approved. Imclone chose to do the shortest, smallest trial they possibly could get away with, and it backfired on them. One reason for that trial design was to be able treat cancer patients more quickly - that's a huge motivating factor for everyone in the field, and I don't want to minimize it. But another reason for Imclone's hurry is the hoofbeats that they can hear coming up behind them. They need this drug to be first to market. Bristol-Meyers Squibb, for their part, is already on the hook for two billion dollars for only 40% of the drug's profits. And every delay decreases their chances of ever earning that money back.

Comments (0) + TrackBacks (0) | Category: Cancer

Who Dares, Wins?

Email This Entry

Posted by Derek

I'd like to take the time to sympathize with Elan Pharmaceuticals over what's happened to their Alzheimer's trial. They had the initiative (and the nerve) to pick up and run with an unusual discovery: that a protein that precipitates in the brains of Alzheimer's patients, beta-amyloid, can be attacked by an immune response.

I'm not going to take sides in the "does amyloid cause Alzheimer's, or does Alzheimer's give you amyloid" controversy. Most money is on the first choice, but there's a vocal minority for the second that makes some good points. At any rate, the idea of going after amyloid deposits by raising antibodies to them was pretty gutsy.

In general, you want to think twice about raising an immune response to one of your own proteins. It's like the old rule of black magic - don't call up anything that you don't know how to send back down. It seems, though, that amyloid, weird and insoluble stuff that it is, looks useless and foreign enough that it can be treated as an invader.

The brain is also considered an immune-privileged organ. You wouldn't have high hopes for a vaccine approach to work there. But they actually cleared amyloid deposits from the brains of rodents (in a special strain bred to have amyloid problems.)

Elan took this into human trials as fast as they could. Unfortunately, they've run into what some feared might be the downfall of the whole approach. Several patients are showing signs of central nervous system inflammation. The immune response appears to have gotten out of hand.

There may be a way to fix this, but it'll be a while before anyone is able to try this approach again. A lot of ground work will have to be done first. It's a pity, because this had the potential to be a home run against a disease that's consumed minds, lives, and a vast amount of research time, money, and talent.

Comments (0) + TrackBacks (0) | Category: Alzheimer's Disease

February 26, 2002

A Certain Tension in the Air

Email This Entry

Posted by Derek

Well, today is Imclone day at the FDA (see Jan 31 and Feb. 6 postings.) All parties will be meeting to decide what the path forward is: reworking the existing data, supplementing it with whatever else the companies can dredge up, or new clinical trials.

Analysts have raised the possibility of using some clinical data from Merck KgaA (German Merck, not the US company.) They're the licensees in Europe. But most of their data is for head and neck cancer, which won't cut it for Imclone's colon cancer application. Merck has apparently done a couple of small trials in colorectal patients, but most of their data for that indication's European filing was supposed to come from Imclone. There might not be enough new data to salvage things, considering how negative the FDA was the first time around.

If Imclone gets to reapply without new data, I'd chalk that up to the work of experienced regulatory-affairs people from BMS. I assume they've brought in everyone they can find. Of course, that brings up the question of where those folks were for the first filing, doesn't it?

I wouldn't be surprised if it turns out to be new trials, which is of course what the companies want to avoid. If that happens, look for more now-we're-really-mad statements from BMS, and another round of nasty press releases.

The pity of all this is that Erbitux very likely works. That puts pressure on for approval. You already see comments about the mean ol' FDA hasseling this small company with their wonder drug, but that's missing the point. If you want to get mad at someone, get mad at Imclone for doing the absolute minimum they thought they could get away with. And get mad at BMS: I still think they should have caught this before it went to the FDA at all.

Comments (0) + TrackBacks (0) | Category: Cancer

New Drugs for HIV

Email This Entry

Posted by Derek

Megan McArdle points out the recent news (which has shown up in Tuesday's NY Times and other outlets as well) about new HIV treatments with possibly fewer side effects. She asks if the same technique can be applied to other diseases, and I thought for the benefit of the non-pharma audience that I'd go into some detail on that.

Actually, there's no particular new technique involved - just good ol' drug development. These compounds work by different mechanism than the stuff we've had so far. Here's a (fairly) quick explanation, centering around one of the therapies highlighted in the press reports, the one from Schering-Plough.

The specific target of that compound is a protein called CCR5, which sits straddling the outer membrane of some types of cells. Part on the outside, part loops to the inside. It's one of a huge class of proteins called receptors, whose lot in life is to latch onto specific other molecules if and when they come by. When they do, that binding event sends a signal into the cell, and these signals can be tied into just about every cell process you can think of. This is one general way that you can enable some molecule floating outside the cells to set off changes inside them.

The subject, like most molecular pharmacology, rapidly reveals its career-worthy godawfulness on closer inspection. All those things in the above paragraph vary hugely and interrelatedly. To give you an idea, various receptors are a key step in the actions of things as important (and as unrelated) as insulin, cocaine, growth hormone, and caffeine. They're still counting up how many different receptors there are from the human gene sequences, but it's probably going to be in the low thousands when the dust settles.

In the mid-1990s, studies on patients who appeared more naturally resistant to HIV showed that they had a mutated form of CCR5. It turned out that the receptor is one of the things that the virus uses to get into blood cells and infect them, but the mutated form didn't let HIV bind to it very well. That immediately led to the idea of blocking a normal patient's CCR5 with some small drug molecule - if the receptor were stopped up with that, maybe HIV wouldn't be able to bind to it, either.

This receptor-blocking idea is a favorite in drug research. It's usually a lot easier to gum up a receptor than it is to mimic the specific thing that turns it on. That's why everyone jumped on this idea so quickly. So far, it seems to work, and congratulations to the Schering-Plough team for it. Although I haven't talked to them about it - not that they'd tell me anything, either - I know several of the chemists who worked on this project. They and their biology colleagues deserve the success.

But will this lead to a marketed HIV drug? Good question. It's obviously made it through the animal toxicity testing I spoke about the other day, because the compound has shown efficacy in humans. Those are both big steps. Now come more studies, with more patients, to make the case to the FDA. It's not an early-stage drug any more, and the odds are fairly good that it'll make it, but there are still several places where it could banana-peel and slip off the tightrope.

If it does, will it have fewer side effects than the protease inhibitor cocktails? Another good question. Right now the only thing you can be sure of is that the side effects will be different. All drugs, every single one of 'em, have side effects. Some are major, some are minor, and some are minor only relative to the disease that's being treated. Since this doesn't work on HIV protease, it presumably will avoid the problems of those drugs, which is good news. But there could always be others out there waiting.

There could mechanism-based tox, for example. We really won't know until larger, longer trials are conducted what might happen when you block CCR5 for an extended period, what happens when you block it while you're taking other drugs at the same time, or if there's some subset of the patient population that will react unusually.

Or there could be non-mechanism-based tox, which is what happened with the protease inhibitors: keep in mind that (when the research began) no one expected the body-fat remodeling and the other side effects of that class. Those seem to have nothing to do with blocking HIV protease, and arguments rage as we speak about what causes them. Is there some other protease that you can't avoid hitting when you go after the one in HIV? Could be. Is there some totally unrelated thing with (by sheer bad luck) a similar-looking binding site, so that most anything that binds HIV protease will hit it, too? Can't rule it out.

None of these arguments are specific to the HIV therapy field, of course. Investigative drugs go down the tubes all the time for just these sorts of reasons. And sometimes even the large trials aren't enough to catch bad side effects that occur at very low frequency, and you get the serious bad news after the stuff has gone to market. That seems to be what happened with the diabetes drug Rezulin (troglitazone,) and it's not the only example. When that happens, so many lawsuits start flying that it looks like it's snowing.

Am I a gloomy researcher or what? Nah, just realistic. I'm actually fairly perky most of the time, so I'll end on an optimistic note:. What we have now are some new ways to treat a terrible disease. The more routes of attack we have, the better. Along the way, we're learning a lot that can help out in other fields as well. The great thing about drug discovery, about science in general, is that nothing's ever really in vain, and no good work is ever really wasted. It all adds up, and keeps adding up. And what we're building, I truly believe, is the greatest work of the human race.

Comments (6) + TrackBacks (0) | Category: Infectious Diseases

February 25, 2002

All the Not-So-Myriad Ways

Email This Entry

Posted by Derek

The mention of schizophrenia last week brought up something I've thought about since I worked in the field: the limited forms of mental illness. When you first read about insanity (or deal with them firsthand,) it's easy to think that everyone who's insane is sui generis.The varieties of symptoms seem limitless.

But the more I've thought about it, the more I think the opposite. There are only a set number of ways in which humans go insane. Think of any given case of dementia, and you can come up with plenty of similar ones: you have paranoids convinced that their thoughts are being read - by their TV, by aliens, by invisible beams - or that the people they see on the street are all agents. There are the people who let piles of paper and garbage crowd them out of their houses. And the obsessives convinced that they are good friends with, are going to marry, are already married to some celebrity. You'll certainly find differences among these and among the many other types. But they're variations on the same master templates, differences of degree rather than kind.

Contrast the familiar dementias with superficially similar ones that don't seem to exist, like an inverse paranoid: someone who's convinced that people are sneaking around behind his back, helping him out and doing him favors.

Now, the nuts-and-bolts biochemistry of the brain is overwhelmingly complex. That's one of the big reasons that drug development in the field is such a slog. But at a systems level, it may be that there are several broad pathological states that the neuronal net can fall into. These could be based on an uncorrectable excess (or deficiency) of signaling in some part of the network, or some defect of timing in the handoff of processing from one region to another.

It might be analogous to similar low-energy states of a chemical or physical system, local minima on a surface. There could be any number of genetic and/or environmental factors that push the brain into one of these conditions, just the same way that you can tumble into a hole by coming from any direction on the surface. But you end up in one of a set number of places, one defined hole or another.

Comments (0) + TrackBacks (0) | Category: The Central Nervous System

February 24, 2002

Toxicolottery

Email This Entry

Posted by Derek

I'll continue to talk now and then about some topics that won't necessarily be news to those inside the pharma industry. I see from my traffic stats that most of the hits are from outside it, although there are increasing numbers from both my own company and the competition.

Thoughts of work prompt me to quiz non-specialists: at what point do you figure most drug projects fail? Ever thought about that one? You can be sure that everyone inside the industry has, oh yeah. There are plenty of data points to study - the sound of failing projects is this constant clanging in the background.

Failure in clinical trials get the most press attention. They're certainly bad enough to deserve it. You lose lots of candidates in Phase I, because they turned out to be toxic in normal volunteers. (Well, at least toxic in the sort of person that signs up for Phase I studies, but that's another story.) Then you lose some of those non-toxic candidates in Phase II, because they didn't work well enough, or at all. Failure at those stages is particularly expensive and frustrating; it's late in the game. And it means that your animal models turned sour on you somehow, by telling you the compound would be safe and that it would be efficacious.

Your disease models are what tell you the latter, and they vary from target to target. As I mentioned the other day, the ones for CNS ailments are particularly hairy; other fields have it easier (but not easy!) The animal toxicity tests for general safety, though, don't vary much between therapeutic areas. They're a notorious hurdle.

Tox is a long and expensive study, by preclinical standards. It usually calls for the largest batch of your drug candidate that you've made until then, and it's the usually the longest animal study you've run, too. And it makes everyone involved hold their breath, because it's a complete black box.

It really is. That's actually where more projects wipe out than any other, in my experience. We really have no idea what's going to happen. Well, you may have some clue about toxicity based on your drug's mechanism, and you're already braced for that (and hoping it cuts in at much higher levels than you need to show the beneficial effects.) But it's that non-mechanistic tox that's out there waiting for all of our projects, and when it hits all you can do is run for cover. Kidney? This protein isn't even expressed in the kidney, what the. . .liver? But the tests on hepatocytes all came back OK. . .spleen? Who ever heard of a drug showing tox in the spleen? Heck, who needs a spleen anyway? And so on.

As I've alluded to in the past, you can sell just about anything to a big drug company if you promise to do something about the failure rate. If anyone has a bright idea for how to predict toxicity before we go into animals (or, God help us, humans,) then here's your chance to cash in. The management would be thrilled at all the time and money that doesn't go down the pipe. The scale-up chemists would be thrilled not to have to make buckets of loser compounds. Even the animal-rights people would be happy.

Note that the obvious ideas have probably already been tried. But don't be afraid to ask.

Comments (0) + TrackBacks (0) | Category: Toxicology

February 22, 2002

Cartesian Aging

Email This Entry

Posted by Derek

As I mentioned previously, I've been reading the letters of both Kingsley Amis and Philip Larkin. One thing you notice in any Collected Letters book (try Evelyn Waugh's) is old age creeping up on the writers. It's less noticable in Larkin's case; his personality famously made him sound about 70 years old for decades. But with Amis, it's clear that you're reading the thoughts of a young, a middle-aged, and then an old man. This process is chronicled from just outside in his son Martin's book Experience

Don't get me wrong - Amis's letters are wonderful, even the late ones. But a sort of hardening of the personality takes place, kin to atherosclerosis, and it's a common thing to see. What I wonder is how much is due to just plain experience and weariness with the world (seeing the same mistakes being made the same ways, again and again,) and how much has a neurologic base.

Circulatory problems, Alzheimer's (we won't get into the debate about what causes it,) any number of other biological causes affect the number and activity of the neurons. And that, in turn affects higher functions of thought and personality. But that statement broad-jumps over a huge pit of unknown detail. These questions are going to keep everyone in the biomedical sciences busy for a long time, and won't the world be an odd place when answers start to show up?

More on this later. There are many things coming much sooner from modern neuroscience, and we'll have our hands full with those just the same.

Comments (0) + TrackBacks (0) | Category: The Central Nervous System

February 20, 2002

Giordano Bruno

Email This Entry

Posted by Derek

I missed a chance yesterday to note an anniversary. Giordano Bruno was something of a crank, not normally the sort of person I'd be commemorating. But in his time, it didn't take very much to be considered either of those, or worse, and we have to make allowances.

He was headstrong. We can see now that he was sometimes eerily right, other times totally wrong. Either way, many of these strongly held positions were sure sources of trouble for anyone who advocated them. All living things were made up of matter, and that matter was the same across the universe - that one was not going to go over well in the late 16th century.

There was more. The stars, he said, were nothing more than other suns, and our sun was nothing more than a nearby star. He saw no reason why these other suns should not have planets around them, and no reason why those planets should not have life: "Innumerable suns exist; innumerable earths revolve around these suns in a manner similar to the way the seven planets revolve around our sun. Living beings inhabit these worlds."

He went on at length. And as I said, much of it was, by scientific standards, mystical rot. His personality was no help whatsoever in getting his points across. He appears to have eventually gotten on the nerves of everyone he dealt with. But no one deserves to pay what he did for it all.

Bruno was excommunicated and hauled off in chains. He spent the next several years in prison, and was given chances to recant up until the very end. He refused. On February 19th, 1600, he was led into the Campo dei Fiori plaza in Rome, tied to a post, and burned to death in front of a crowd.

Mystic, fool, pain in the neck. I went out tonight to see Saturn disappear behind the dark edge of the moon, putting the telescope out on the driveway and calling my wife out to see. Then I came inside, sat down at my computer, wrote exactly what I thought, and put it out for anyone who wanted to read it around the world. While I did all that, I remembered that things haven't always been this way, haven't been this way for long at all, actually. And resolved to remember to enjoy it all as much as I can, and to remember those who never got to see it.

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

February 18, 2002

A Couple of Days Off

Email This Entry

Posted by Derek

I won't be posting for another day or two; I'm taking tomorrow off from the Wonder Drug Factory and heading out with the family. My chemistry can get along without me just fine, and the people that report to me will most likely be even more productive without me around.

Leaving the lab for a few days was much harder back in graduate school, of course. The main reason was psychological. It took at least six months after I got my PhD for that voice in the back of my head to stop telling me to get back in lab, that I was wasting time. Every hour that I wasn't trying to finish my project was an extra hour that I was going to spend in grad school. This mental nudging didn't just occur when it should have. No, I felt this way when I was doing frivolous stuff like buying food, or putting gas in the car.

The second problem with leaving the lab was that I had a lot of chemistry going on simultaneously. I persisted in thinking that I'd remember every tiny detail when I got back. So I'd return and find a bunch of flasks, helpfully labeled with things like "large batch," "other fraction," or "N." My first day back in the lab always involved a lot of staring up at the ceiling, trying to remember what the heck I was doing.

Of course, many of my days in the lab involved some staring up at the ceiling. The difference was, on those occasions, my lips were moving.

Comments (0) + TrackBacks (0) | Category: Graduate School

February 14, 2002

Modeling the Brain?

Email This Entry

Posted by Derek

That neuroscience business came up, I guess, because I have a minor background in it. I broke into the drug business doing work on schizophrenia, and followed that with several years on Alzheimer's.

If some of the people in the field read this - well, don't take it the wrong way - but I'd almost as soon have a job breaking concrete with my nose. The central nervous system is a very, very hard area to work in. That's partly because brain function is hideously complex: it's an interesting question whether a human brain even has enough ability to comprehend its own workings. But it's partly because a key part of the drug-testing cascade is often missing.

That's animal testing. (And it really is a key part - eventually I'll get into it with the anti-in vivopeople, and I'll argue that position as long as it takes.) The problem with many central nervous system targets is that the animal models either don't exist, or (even worse) exist but are untrustworthy. That last situation is a killer: the models persist because there is a constituency that believe in their relevance. You'll be running into those folks over and over if you try to do without, and they're going to refuse to believe in your drug candidate unless it's been through the wildebeest swim maze, the platypus tail flick assay, whatever.

The models are so hard because you're often trying to affect behavior that is unique to humans - like remembering phone numbers. Whether a rat can remember not to run into the electrified part of the cage is of doubtful relevance. I think that there are many kinds of memory storage, and I don't believe that rats partake of the kinds that we're most worried about. It's true that there must be common molecular mechanisms for all types of memory (at some level) but messing with those processes indiscriminately (the only way we know how, in many cases) is a recipe for trouble. Let's not even get started on the topic of animal models for schizophrenia.

There's been a lot of progress in Alzheimer's the last two or three years. I enjoy reading about it, and I wish everyone working there all the luck in the world. I may need your compounds some day, guys, so keep banging away. But I'm glad that I'm not having to bang away with you.

Comments (0) + TrackBacks (0) | Category: Alzheimer's Disease | Animal Testing

February 6, 2002

Imclone in Progress

Email This Entry

Posted by Derek

The Bristol-Meyers Squibb / Imclone story has taken a real bad-movie turn. (See my postings on this last week if you're not up on this one so far.) BMS has served up an ultimatum that I don't recall every seeing before: Ditch your CEO, or we walk.

Actually, it's even livlier than that: Ditch the CEO, ditch his brother (the chief operating officer,) give us control of your dealings with the FDA. . .oh yeah, and give us a bigger share of the profits from the drug. Or we walk.

It's an interesting threat, and I can't wait to see Imclone's response. Who will back down? You can argue that Imclone has to, since BMS is their best hope to get the drug to market - and at this point, the deal is still better than anything they're likely to get from anyone else. Their stock will sink even lower if BMS actually does walk, putting them in a weak negotiating position.

But you can argue that BMS has to back down, too. They've already sunk 1.2 billion into this, and to walk away after that (with no drug and some rather depreciated stock) would make the shareholders furious. (It's not like they're in a good mood already, although the tough talk must have cheered everone up.) And if they leave, their cancer pipeline is status quo ante- that is, still in the shape that made them think they needed to spend billions to improve it fast.

Much as I think that Imclone deserves what's happening to them, it doesn't take away from the fact that BMS didn't investigate this the way someone spending a billion dollars should have. There must be some pretty embarrassing PowerPoint presentations left on people's hard drives, talking about what a great job everyone's doing on the clinical and regulatory end. Eventually, BMS is going to have to figure out how this mess could have happened. It won't be easy, since everyone who even got close to the deal is probably hiding behind their nearest tree.

My prediction is that Imclone, with great protesting, will end up agreeing to almost all the terms. They might salvage some of the milestone payments that BMS wants to get rid of, or be able to talk them down a bit on their profit-percentage demands. But getting Erbitux through is probably their only hope for survival, and BMS is probably their only hope for getting it through.

Comments (0) + TrackBacks (0) | Category: Cancer

February 5, 2002

Why Total Synthesis?

Email This Entry

Posted by Derek

So why do huge natural product molecules still get made, if the thrill is gone?

Well, for one, not everyone agrees about the thrill. Total synthesis is one of the areas with real summits to plant flags on, and you really can be the first to climb them. And (unlike mountaineering!) you don't run out of mountains. They keep on coming, higher and trickier, year after year. Of course, as I went on about on Sunday, the technology keeps on improving, too. I'd argue that we're getting close to an expertise that allows us to hack our way up most any molecular mountain, one way or another.

Another reason the work goes on is that it used to be a great way to find totally new chemistry. Back in the day, you often had to invent new reactions just to have a chance of making these molecules, and that was one of the main justifications for the whole effort. Unfortunately, now that we don't necessarily have to invent the new reactions, many total-synthesis types don't.

I don't want to exaggerate, because it's still no cookbook. Many steps in a big total synthesis require lots of tricky modifications from the normal way you'd run a reaction. And there are lots of reactions that should work and don't; the first thing out of the book usually doesn't do the trick. But, still, very seldom now is new chemistry invented during a major synthesis. People will discover a new reaction, and think of a natural product to demonstrate it with, but they won't discover the new reaction in media res.

That's because it takes too long to do it. The advances in the science are making it gradually trickier to find totally new reactions, or new applications of old ones. If you're in a race to be the first to synthesize Megatoxin, you're not going to spend a few months (or a few years) to see if you can come up with a new reaction that'll save you six steps. You'll just hack out the six steps and get on with it - even if no one else is racing you, which is almost always the case these days.

There's one reason, though, that I can't argue with. Total synthesis is a great way to train chemists. You have non-stop problem-solving under very trying conditions, you experience all sorts of chemistry, and you end up with the hands to do just about any reaction there is. The drug companies love to hire total synthesis people. They figure (correctly) that dealing with the adversity of that work is good training for drug discovery, where most things don't work, either.

Comments (0) + TrackBacks (0) | Category: Chemical News

February 3, 2002

Climbing Mountains

Email This Entry

Posted by Derek

I mentioned the team-of-Sherpas approach to making molecules, but that's something that (fortunately) I haven't had to do much in recent years. In drug discovery, we try to avoid anything involving that kind of chemical labor - the rest of the drug development stuff is enough to keep everyone busy, thanks. Contrast that to some academic organic chemistry, where molecules that need pyramid-construction-size teams are sometimes the whole point.

I did big-molecule natural product synthesis for my PhD, and I don't miss it for a minute. (I don't miss a lot of things about my PhD for a minute, for that matter, but that's another story.) It's a specialized world inside organic chemistry, which during its glory days was for many the only world that mattered. It's hard to put exact dates on that, but you could start in the 1950s, end sometime in the late 70s or early 80s, and not set off too many arguments.

It's not that huge and difficult molecules aren't made any more. They are, and some of them are weird enough to have made the old titans like R. B. Woodward choke on their Scotch. But it's different somehow; I think it's because we've gotten a little too good. There are a lot of reactions we can pull out now that Woodward's generation never lived long enough to see, reactions that do things they never knew could be done. So now, when some massive team of postdocs makes Voodoomycin, Whateverol, or some other molecule that looks like your structure-drawing program malfunctioned all over the page, it doesn't set off the awe that the older syntheses did. It can't. There are dozens, hundreds, thousands of people who look at the resulting paper and say "Hey, give me a team of fifty smart, highly trained workaholics and a million dollars from NIH, and I'll make Whateverol, too."

We can make almost anything (given enough sweat, time, and money,) but most complex molecules still use up far too much of all three. It's not the boundries of the science that hold us back any more, just the boundries of the real world. Those who aren't well acquainted with the field figure it can do most anything, but those inside it know, for practical reasons, that we often can't.

Comments (0) + TrackBacks (0) | Category: Chemical News

February 1, 2002

Medicine Man

Email This Entry

Posted by Derek

I can't talk about rain forest drug discovery without mentioning the (pretty bad) 1992 Sean Connery movie Medicine Man. He plays an alleged biochemist who comes up with a Miracle Drug, more or less by finding it under a leaf.

Plenty of large and small stuff is misportrayed, but I did say it was a movie. (One of these days someone will have to make a list of jobs that movies actually get right.) The part of this one that drug discovery people particularly enjoyed, though, was when some crude extract is fed into an impressive device that immediately displays the structure of the active compound. "I want one of those!" was the universal reaction.

I believe that this was supposed to be the one active component of a complex mixture, the plot hinging on being able to find it and isolate it. Of course, Shaman's business model (see previous post) depended on being able to do this sort of thing, and you see where it got them.

I only wish we could find things out as suddenly and dramatically as they do in films like these. As is true in most areas of research, medicinal chemists spend a fair amount of time looking at printouts (or up at the ceiling tiles,) wondering just what the heck happened in the last experiment. Determining chemical structures is easier than it's ever been (read: in most cases, it's possible to do it), but for natural products it still isn't trivial. My Connery-ometer remains on back-order.

Comments (0) + TrackBacks (0) | Category: Analytical Chemistry