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: Twitter: Dereklowe

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July 31, 2007

Incomprehension, Out For A Stroll

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Posted by Derek

Here's a little night-time journey through Genentech's Vacaville manufacturing site, through the eyes of someone who has no idea of what he's seeing. The problem is, he doesn't know that - he and his friend think that they have it all figured out:

"On the one hand this place makes drugs that save people's lives -- treatments for cancers and cystic fibrosis and asthma," she told me. "Heading out," I told her, as the construction worker walked across the campus towards the gate.

"And yet, on the other hand, this place is pure evil." We walked past large vats labeled "Poison" and huge machines that looked like they could crush us. Smoke belched from the top of the building and we could see more buildings and a parking lot in the distance.

"Companies like this are made up of dozens of people, each of whom, individually, are the sweetest guys. Nice, friendly people who just care about doing well at their work." As we approached the buildings, we saw that even now -- 2AM -- the place was alive. New cars were pulling into the lot and men and women were walking from building to building. The yellowed light on their white lab coats gave the whole thing a sinister air.

"And yet, together, they manage to pull off the most incomprehensible evils. . ."

Well, incomprehensible to Aaron Swartz and his friend, anyway. The essay is written as a feeble imitation of Hunter Thompson's "Fear and Loathing in Las Vegas

Swartz presents himself through the whole piece as a passive, puzzled observer. It all just seems too much for him - equipment he doesn't recognize, people doing things he doesn't understand for reasons that he can't quite work out. The Genentech scientist in the piece comes across as a much more human figure, although there's some attempt to make him a figure of fun. Which reminds me - if anyone out there works at the Vacaville site, or knows someone who does, I'd be interested in hearing from anyone who witnessed this tiny adventure from another perspective).

Aaron Swartz, by the way, was one of the early people behind the social media site Reddit, which is intermittently interesting. These days, though, it's more often a swamp of delusional conspiracy groupthink. If it were your only news source, you'd likely be convinced that (among many other unusual things) storm troopers were sweeping the streets, rounding up supporters of Ron Paul. Or, perhaps, that Genentech was run by creatures out of H. P. Lovecraft.

Comments (14) + TrackBacks (0) | Category: Why Everyone Loves Us

July 30, 2007

Avandia's Latest Round

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Posted by Derek

I have to say, I think the FDA vote on Avandia (rosiglitazone) was well done. As those following the story know, David Graham at the agency had been pushing to have the drug removed from the market, but a panel just voted 22 to 1 to keep it, albeit with warning labels and stricter standards for use.

That's as it should be. As mentioned here before, we really don't have hard enough data on the compound's risks yet and whether or not they outweight its benefits. I think that this decision is a grown-up one: to say that yes, rosiglitazone appears as if it may have some cardiovascular risks, but since we're not sure about that, for now it appears that they're risks worth taking. It'll be up to patients and their physicians to make the call.

Would that it always worked this way! Drugs have side effects, how ever much we might wish that they didn't. Some are bad enough to wipe out any benefit, and some aren't. It's a judgement call every time, and I'm glad that the panel exercised some instead of going reflexively with the "no risk to anyone for any reason, ever" mindset.

Avandia may well be taken off the market when more data come in. And if that happens, then we'll know that it was the right decision. But we don't know that yet. How, I wonder, will this vote affect the lawsuits that are already being prepared? Can you sue for being (allegedly) harmed by a drug the FDA just re-reviewed and decided to keep?

Comments (19) + TrackBacks (0) | Category: Toxicology

July 27, 2007

You Discover It, We Sell It. Deal?

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Posted by Derek

There was a comment to the previous post which asked an interesting question: if you look at the best-selling drugs in the portfolios of the major companies, what percentage of them were developed in-house?

I'm sure that someone has already done this analysis, but I haven't been able to lay my hands on it. But in some cases it's a rather embarassing figure - Pfizer, for example, which brings up the question of how you define "in-house" when the house keeps expanding. The rigorous definition - a project (and chemical matter) that started inside the company and went all the way to market - is probably the way to go. A drug that came about through buying a compound, a target, or a whole company doesn't qualify.

It's impossible to talk about this without someone bringing up the idea of a virtual drug company - one that doesn't do any of its own discovery research, but exists to do clinical, regulatory, and marketing. This ideas has been kicking around for fifteen or twenty years that I know of, and probably longer. The best argument I can make against it is that no one's tried it yet. I'd be very surprised if this hasn't been seriously looked at and rejected.

My strong suspicion is that when you run the numbers (how many compounds are available, how much they'd cost, etc.) that you can't quite make it work. Bidding is already expensive for the good stuff, and a company that tried to live only by buying things in would often find itself paying the highest prices possible. And that's assuming that there were enough compounds out there in the first place, no matter the price, and I have my doubts about that, too.

Comments (28) + TrackBacks (0) | Category: Drug Development | Drug Industry History

July 25, 2007

From the Sequencer to the Drugstore?

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Posted by Derek

A science writer who's read this blog for some time asked me a question which I thought I'd throw out to the readership. I was, in yesterday's post, making reference through gritted teeth to the amount of money the drug industry spent on genomic approaches. So here's the question, verbatim: "What drugs, if any, have been developed thanks in large part to insights gleaned from the human genome project?"

I don't think we're going to have to use many fingers, personally, given what I've seen. The "in large part" clause will take care of a lot of tangential cases that have been claimed mostly for PR purposes. There may be some dispute about the word "developed", since it could still be early for something to be hitting the market from the time of the Human Genome Project. Let's take that to mean "shown substantial and continuing clinical progress".

And I realize that there's room to argue about the "human genome project" part of the question, too, since many small companies (deCODE, Millennium, Incyte, etc.) did a lot of work of their own outside of the official HGP. But for argument's sake, let's throw the question open to all the genomic approaches. Examples?

Comments (16) + TrackBacks (0) | Category: Drug Development | Drug Industry History

July 24, 2007

Godzilla vs. Mothra? Relman vs. Epstein!

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Posted by Derek

Arnold Relman is back. The co-author, with Marcia Angell, of The Truth About The Drug Companies, has a long review in The New Republic of Richard Epstein's new book on the industry, Overdose.

Not everything in Epstein's book is right, and not everything in Relman's review of it is wrong. But when Relman misses, he misses big. Take, for example, this:

"Indeed, the industry's greatest enemy is itself. Innovation by the major pharmaceutical firms has certainly fallen off sharply in recent years, but there is good evidence that the cause lies with the industry's own policies rather than with government regulation. The drug companies are being driven more by financial ambition and marketing considerations than by scientific or public health objectives, and that is the root of their current problems."

That must be why we plowed all that money into genomics, among other technologies: marketing made us do it. I knew we'd track down the culprits eventually! OK, Relman's targets here are the "me-too" drugs, which I've written about many times on this site. I get the strong impression that he underestimates the cost and difficulty of developing these - he seems to think that it's pretty much a breeze once the first drug in a class has hit the market. Actually, to my mind, one of the main advantages companies are seeking in a me-too is that the first drug has proven that a market exists, and that its mechanism actually works. The development costs for the later drugs, though, aren't hugely cheaper than for the first one. And, I might add, they still don't always work.

Inside the industry, people spend a lot of time talking about why productivity has gone down (we're in agreement on that point). But you don't hear many people advancing Relman's pet thesis, that we're spending too much time chasing each other. That's because I think he's confusing cause and effect a bit: we're not unproductive because of the me-too drugs - we're making me-too drugs because a lot of our other stuff doesn't work.

Believe me, companies would love to come up with new therapies for underserved markets - Alzheimer's, say - or to come up with anticancer compounds that would do for the many what the likes of Gleevec do for the few. And we'd certainly make money at these, too - if we could find a way to do them. Saying that it's for lack of trying just doesn't ring true.

That mention of making money brings up another favorite part of Relman's review:

"Regardless of the disease it targets, and whatever the benefit, no one has ever adequately explained exactly how the "value" of any new drug can be translated into dollars. It seems more likely that the price of newly approved patented drugs is simply set at whatever the manufacturer believes the market will bear. "

Good Lord! Where will it end, if companies price things according to what they think that people will pay for them? I look forward to the establishment of the Relman Board, which will determine, by means doubtless beyond my abilities to understand, the True Price (trademark applied for) of all drugs. Problem is, Relman himself probably looks forward to that, too. . .

Comments (23) + TrackBacks (0) | Category: "Me Too" Drugs | Drug Industry History | Drug Prices

July 23, 2007

Deactivation, After All

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Posted by Derek

Four years ago I wrote about an unusual Roche diabetes compound targeting glucokinase. The odd thing about it was that it made the enzyme more active, which is something you can only rarely hope to do. Enzymes generally run near the top of their specs, unless there's some built-in switch that keeps them damped down until they're needed. That's often phosphorylation, but another trick inside the cell is to keep the concentrations of substrate low (or the concentrations of some inhibitor high). But once they go, they usually go about as fast as they can. This glucokinase example is still about the only one I can think of in drug development, and it's had a fair amount of attention over the years.

Maybe I should switch the tense, though, because reader Daniel H. has informed me that Roche seems to have stopped work on the compound in Phase II. The company had taken their lead compound (R1440) through several different trials, so something seems to have been working, but they don't seem to have given any reasons as to why they abandoned it.

After that much Phase II work, the most likely answer is some sort of toxicity, the kind that comes up too close to the efficacious dose. A company may try several different dosing regimens, combinations with other drugs, or patient populations trying to get around a problem like that, and perhaps what we're seeing is the end of the line. Nothing looked safe enough to spend the really large money on Phase III.

By now, there are several other companies in the same area, and I'm sure they're rather curious about all this, too. Is glucokinase activation dead as a target? As with many questions in this industry, you'll have to have either a lot of money or a lot of patience to find out. And if you want to come down and try drug development yourself, you'll need a lot of both.

Comments (2) + TrackBacks (0) | Category: Clinical Trials | Diabetes and Obesity | Drug Development

July 22, 2007

A Farewell to Tin

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Posted by Derek

I was browsing through the posts at Totally Synthetic, which is now my substitute for looking at total synthesis papers in the primary literature, and came across this question:

"However, this brings me to a point of consideration - why are Stille coupling (reactions) more common in academic publications, and Suzuki more so in an industrial/commercial context?"

(For the non-chemists in the audience, these two reactions are ways to skin what is basically the same cat - forming carbon-carbon bonds on a particular class of starting materials). And this is one of those questions with a one-word answer, and in this case you can pick your word. Either "tin" or "toxic" would work just fine. The Suzuki uses boronic acids or esters, which are generally water-soluble and nonpoisonous. The Stille reaction, although it has a reputation for working on small scale in finicky, highly functionalized molecules, uses organotin compounds. These are highly nasty, and very difficult to completely remove from your final compound. If your final compound is going to be something that people are going to put in their mouths, which is our dearest hope in the drug labs, you're just not going to use tin.

And I don't mean that you'll tend to avoid it, or only use it when other things don't work as well. You just won't touch it. I'm not aware of a single pharmaceutical process which uses an organotin reagent, and I'm not holding my breath for one to appear, either. There are a lot of other reagents in this category: things that you basically have to edit out of your repetoire.

Obvious farewells are made to things like nickel carbonyl, which a lot of people in academia don't want to use, either. But in drug research, a lot of people decide to ditch their old grad-school favorites like HMPA, a solvent that can make some reactions work when little else can. But if your compound can only be made using HMPA, is it going to be a drug? Highly, highly unlikely.

Naturally, one way around this difficulty is to assume that the process chemists are going to fix this little problem later on if your compound goes ahead. But your compound isn't going to go ahead, chief. Something nearly as good as your candidate has surely been made in the course of the project, something that doesn't use HMPA. It'll win. You're honestly better off trying something else in the first place and not wasting your time. And the same, exactly the same, goes for the Stille reaction. Enjoy it in the universities, folks. If you go on to industry, you won't be seeing it again.

Update: Check the comments - there are some well-informed disagreements!

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

July 19, 2007

Hype In Spaaaace!

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Posted by Derek

This week's award for the most straight-faced research whopper goes to. . .the government of Brasil, of all the possible candidates. In their attempts to bounce back from a disastrous explosion at their launch site a few years ago, the Brasilians have successfully fired a sounding rocket with an experimental payload.

I'm not quite sure what exactly was in these experiments - from press reports, it looks like some enzyme kinetics and some DNA repair studies. Both of these were to be looked at under microgravity (aka free fall), which I have to say does not sound like a very fruitful area of research to me - of all the forces that affect enzyme behavior, gravity seems like one of the least likely to show any effects.

And there's the problem that (since this was far from an orbital flight) the payload experienced only about seven minutes of free fall. With a faster enzymatic reaction, you might be able to run something similar on a "Vomit Comet" airplane flight, frankly. And as for the DNA repair work, that was to be after exposure to ambient radiation, which no doubt can be simulated quite well on the ground. But that wouldn't be so good for publicity and national pride, would it?

So, what will these experiments lead to, you ask? I'll let the experimental coordinator field that one, although you may well have guessed the answer already: "Eventually, the results could help us develop new processes and pharmaceutical products to treat cancer." Well, sure - with a sufficiently open-minded definition of the word "eventually". And the word "treat". And probably the word "new", and while we're at it, the word "results" as well.

Comments (17) + TrackBacks (0) | Category: General Scientific News

July 18, 2007

Over There, Behind That Stack of Whatchamacallits

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Posted by Derek

Laboratories are not immune to a problem that affects many a kitchen. Surveying the counters and the cabinets, ones eye falls on a space-filling gizmo that hasn't been used in months, and the thought comes up before it can be repressed: "I wish I hadn't bought that thing".

As scientists, we don't have late-night infomercials to blame: the fault is not in our cable packages, but in ourselves. A likely way for white elephant equipment to get in the door is by the efforts of someone who used it somewhere else and just loved it. They agitate for it, they get the authorization to buy it, they order it. . .and, likely as not, only they ever use the thing. No one else likes/feels the need/can be bothered to learn how to use it. The advocate eventually moves on, but their hardware, perforce, stays behind.

These things migrate to unused fume hoods, should any exist, or to bench areas so inconveniently located that no one ever occupies them. This natually helps to ensure that no one uses the apparatus again, since it's now so far off the jungle paths. Should anyone try, they often find that vital pieces and accessories have been shed along the way, along with chunks of the documentation.

Biology labs are particularly laden with these things, in my experience. In chemistry, the combichem craze of the 1990s left a lot of stuff washed up on the beach, as did the proliferation of (semi)automated reaction stations and multiple-simultaneous-reaction gizmos. But none of these items are useless - it's just that some of them aren't quite useful enough for the space they take. By the time some of them get thrown out, you can tell how old they are just by the color of their plastic housings and the fonts used for their brand names.

Comments (27) + TrackBacks (0) | Category: Life in the Drug Labs

July 17, 2007

Visfatin: Real Or Not?

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Posted by Derek

A commentor to my Proteomics 101 post the other day brought up an important point: that before you can have a chance to figure out what a protein is doing, you have to know that it exists. Finding the darn things is no small job, since you're digging through piles of chemically similar stuff to unearth them. What's more, we can't just ignore 'em: some of the low-concentration proteins are also correspondingly important and powerful.

Nasty arguments can erupt over whether a given protein and its proposed functions even exist. Crockery is flying over one of those right now, an insulin-like protein hormone dubbed "visfatin" by its discoverers in Osaka a couple of years ago. Well, in this case the protein probably exists, but does it do what it's advertised to do? An insulin mimic secreted by fat cells would be worth knowing about, but there doesn't seem to be enough of it present in the blood to do much of anything, given how well it binds to its putative targets. There are also reports that some of that data in the Osaka paper are hard to reproduce.

Complicating things even more is the (apparently well-founded) contention that visfatin is a re-discovery of a protein already known as PBEF, which is identical to another protein named Nampt. (Each "discovering" group assigned their own name, a situation that happens so often in biology that people don't even notice it any more).

The whipped topping on the whole thing is a accusation of misconduct by someone in Japan, which led to an investigation by Osaka University, which has now recommended that the original paper be retracted. Its lead author, Iichiro Shimomura, does not agree, as you might well imagine. The points of contention are many: whether the misconduct was real at all, or whether it describes real events that don't rise to the level of misconduct, or whether the conclusions of the paper are invalidated or not by them, and so on.

An early solution appears unlikely. And we still don't know what exactly visfatin/PBEF/Nampt is doing. Next time you wonder how things are going over in the proteome, consider this one.

Comments (4) + TrackBacks (0) | Category: Biological News | Diabetes and Obesity | The Dark Side

July 16, 2007

European Drugs, American Drugs

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Posted by Derek

I don't know how many people here in the US have noticed, but the European Community is getting worried about how well its member countries are doing in drug research. Their Pharmaceutical Forum group has met twice so far, trying to recommend changes in drug pricing, rewards for innovation, information transfer to patients, and other areas.

I'll let one of the co-chairmen, Guenter Verheugen, explain the problem:

". . .The time has passed that Europe was the pharmacy of the world. True, our industry still has an inherent strength. But we are losing competitive ground to the United States and, increasingly, to China, India, Singapore and others. There are many worrying signals. Let me mention just two:

First, the widening gap in pharmaceutical research: Over the last 15 years investment in pharmaceutical R&D has been growing in the US significantly and consistently faster than in Europe.

Second, the development of key medicines: In the past, Europe was leading in developing the most successful breakthrough pharmaceuticals. This trend has reversed. In 2004, two thirds of the 30 top selling medicines in the world were developed in the USA."

All of the things the group is looking at seem worthwhile. But I wonder how many of them will do anything to actually change that trend? Phrases like "fair reward for innovation" and "alternative pricing and reimbursement mechanisms" point to one that might. These seem to be carefully worded calls to let the drug companies make a bit more money, in the hopes that they might find it worthwhile to make some more drugs.

That's bound to help. It's true that the United States market is where the money is made in this business, and it can't be a coincidence that this is where a lot of the innovation is coming from. But you can always develop a drug in Europe and sell it in the US, right? No, I think that there are other factors at work, cultural ones that no high-level multinational task force is going to pin down.

Perhaps I think this way because I used to work for a European company, and now work in Cambridge (home of a zillion startups). But I've long thought that there's a different attitude to research and development in this country, a greater willingness to try odd ideas and to put money behind them. I'm not saying that you don't find innovation in Europe, because you certainly can. But I think that innovators have, on the average, an easier time getting funded and being taken seriously over here. It's not a huge difference, but it's a steady one, and it's been compounding over time.

Comments (21) + TrackBacks (0) | Category: Business and Markets | Drug Prices | Who Discovers and Why

July 15, 2007

Proteomics 101

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Posted by Derek

Over at the entertaining culture-blog 2Blowhards, the comments to this post (on people who feel deficient in math ability) include a mention of proteomics, which prompted Michael Blowhard to say:

"Proteomics" -- even the word is scary. I wonder how people in the field are going to communicate the substance and importance of what they're up to to civilians ... A challenge, I guess."

A challenge that I'm willing to take up! It's not my exact field, of course, but close enough. I'm starting a new category for posts like this, when I (and the readership here, in the comments) try to explain some technical buzzword-laden area in language that intelligent non-scientists can profit from. So. . .proteomics.

The place to start, most likely, is where the word came from. It's a direct steal from "genomics", the study of genomes, which are the total DNA sequences of a species (or individuals of a species). Back a few years ago when the human genome was being sequenced for the first time (all the individual A T C G letters being read off), it became clear that the number of genes that humans carry around was very much on the low side of what most people expected. (The human genome, as we have it today, is a composite - the number of people in the world who have their complete genome read can be counted on one hand. That's going to change drastically in the years to come as the process gets cheaper, faster, and more useful).

The reason why people expected more genes relates to what a gene is: a stretch of DNA that's read off (transcribed) and turned into a specific protein. That's DNA's job; it's a set of coded instructions to make proteins. But, as it happens, we have a lot more different proteins than we have genes. Clearly, something more happens downstream of the DNA part of the process.

A lot of things happen, actually. Those first-made proteins get altered in all sorts of ways. The same protein can be folded into different shapes, for starters (we're just now recognizing how important a process this is in some diseases). Proteins can also be clipped into smaller ones by many different routes, and at any stage they'll be decorated with molecular tinsel like sugars and lipids and phosphates. All of those can totally change a protein's function. This gives you some idea of where all that diversity is coming from - and why sequencing the human genome, huge and necessary accomplishment though it was, was nowhere near the end of the story.

Proteins spend their time interacting with other proteins. If you think of a cell in your body as a large irregularly shaped bag, full of intricate (and somewhat squishy) 3-D jigsaw pieces which are constantly sluicing around assembling or sliding past each other, you'll have a pretty reasonable idea of what it's like in there. Any given cell will contain thousands upon thousands of different proteins, many of which are doing multiple jobs depending on the time and place. Proteomics is the attempt to understand which proteins are doing what, when, with whom, and why.

It hardly needs saying, but we're just at the very beginning of that study. We have some tools to track these interactions, and they're far better than anything people had twenty or thirty years ago, but they're still rather crude compared to what we need. Huge signaling networks get uncovered and extended, and are found to touch upon others for reasons that are unclear. All sorts of feedback loops and backup systems are sketched in, and many pathways have been missed (or, alternatively, assigned too much importance) because they only operate under certain special conditions that our assays may overemphasize or skip entirely.

This project is much harder than the deciphering of the genome, and will take much longer. But that's because it's much closer to the real-time workings of a living organism, which means that comprehension, when it comes, will be still more valuable. Really substantial sums are being spent on this stuff, along with serious brainpower and computing resources. Progress will be jerky, irregular, infuriating, and of very great interest indeed.

Comments (20) + TrackBacks (0) | Category: Pharma 101

July 13, 2007

Pour Encourager Les Autres

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Posted by Derek

There have been a couple of drug safety issues here in the US over the last few years - you may have heard about one or two of them. Less well known, unless you're in the industry, have been the fines that some companies have paid for deficiencies on their manufacturing end. Schering-Plough's $500 million dollar one about five years ago is one of the most memorable, but there have been others.

But other countries have different approaches to drug safety. And if their regulatory apparatus breaks down in some way, they have, well. . .different approaches to enforcement. Don't look for a Washington think-tank to advocate this method any time soon, although there are times that I'm really glad that it won't come to a vote.

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

July 11, 2007

First Impressions

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Posted by Derek

Cambridge takes some getting used to, that's for sure. In some parts of town, it's a safe bet that most of the buildings you see are filled with people holding up flasks and staring at them with irritated expressions. The small one-story sites generally house firms that no one much has heard of, sometimes several of them to a building. Then there are the mighty research palaces of Novartis, Amgen, and the like, which manage to state in glass and brick (as clearly as any words could) what black ink will do for you as opposed to red.

New Jersey, where I started out in the industry, has plenty of people in the industry. But the atmosphere was different. Perhaps it was the way that the companies were more spread out into different towns: against a densely populated background they didn't stand out as much. Perhaps it was just some essential Jerseyness that diluted things - after living there for eight years, I wouldn't rule that explanation out.

I do remember my wife and I having dinner at a Japanese restaurant near our house and hearing the table next to us discussing problems with a radioactive assay protocol, but that sort of thing didn't happen as often as you'd think. But here the techno-geek vibrations travel pretty much unimpeded, which is fine with me. . .

Comments (18) + TrackBacks (0) | Category: Drug Industry History

July 10, 2007

Travels In Numerica Deserta

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Posted by Derek

There's a problem in the drug industry that people have recognized for some years, but we're not that much closer to dealing with it than we were then. We keep coming up with these technologies and techniques which seem as if they might be able to help us with some of our nastiest problems - I'm talking about genomics in all its guises, and metabolic profiling, and naturally the various high-throughput screening platforms, and others. But whether these are helping or not (and opinions sure do vary), one thing that they all have in common is that they generate enormous heaps of data.

We're not the only field to wish that the speed of collating and understanding all these results would start to catch up with the speed with which they're being generated. But some days I feel as if the two curves don't even have the same exponent in their equations. High-throughput screening data are fairly manageable, as these things go, and it's a good thing. When you can rip through a million compounds screening a new target, generating multiple-point binding curves along the way, you have a good-sized brick of numbers. But you're looking for just the ones with tight binding and reasonable curves, which is a relatively simple operation, and by the time you're done there may only be a couple of dozen compounds worth looking at. (More often than you'd think, there may be none at all).

But genomics/metabolomics/buzzwordomics platforms are tougher. In these cases, we don't actually know what we're looking for much of the time. I mean, we don't understand what the huge majority of the genes on a gene-chip assay really do, not in any useful detail, anyway. So the results of a given assay aren't the horserace leader board of a binding assay; they're more like a huge, complicated fingerprint or an abstract painting. We can say that yes, this compound seems to be different from that one, which is certainly different from this one over here but maybe similar to these on the left - but sometimes that's about all we can say.

Of course, the story isn't supposed to stop there, and everyone's hoping it won't. The idea is that we'll learn to interpret these things as we see more and more compounds and their ultimate effects. Correlations, trends, and useful conclusions are out there (surely?) and if we persevere we'll uncover them. The problem is, finding these things looks like requiring the generation of still more endless terabytes of data. It takes nerve to go on, but we seem to have no other choice.

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July 9, 2007

Now With Ethyl Mesylate!

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Posted by Derek

One of the stories I missed while on hiatus has been Roche's recall of antiretroviral Viracept (nelfinavir) tablets. As readers may know, a problem with many batches of the drug became known in June. It's a mesylate (aka methanesulfonate) salt, but some of the tablets turned out to have ethyl mesylate in them as well, which is definitely sonething I'd go out of my way to avoid ingesting. A worldwide recall (except for North America, which is on a different supply chain) has been the result.

Methanesulfonate is a very happy anion, which is one of the reasons why methanesulfonic acid is used to make salts of basic drugs. The ions of these formulations tend to not be too tightly bound or paired, making the salt forms generally easier to dissolve. (The stronger the interactions between the ions, the harder it is for water to break up the party and dissolve them). But the contentedness of the sulfonate anion makes it a good leaving group when it's part of a covalent molecule. It would rather be off floating around with a negative charge on it again than be tied up in a regular bond, so sulfonate esters and the like tend to be pretty reactive.

Alkyl mesylate esters, then, are also pretty toxic. Just how toxic is the question, though. The stuff will react with nucleophiles wherever it finds them, and if that's some protein on the surface of a soon-to-be-shed epithelial cell, then no harm done. But there are many other situations that won't work out so well, going all the way up to DNA damage.

So how did this nasty stuff get in there in the first place? When I heard about the contaminant, my first thought was that someone had been washing out the reactors where the salt was formed with ethanol, and that appears to be exactly the case. Alcohol plus free acid under strong acid catalysis will give you ester, in what's literally one of the oldest reactions in the book. Roche appears to have been able to keep the contaminant down below regulatory levels normally, but someone's mind has been wandering over in Switzerland. In consequence, the fearsome Swiss reputation for purity and consistency takes a torpedo below the water line.

Comments (6) + TrackBacks (0) | Category: Infectious Diseases | Why Everyone Loves Us

July 8, 2007

Starting Up Again

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Posted by Derek

I'm back! This entry comes from temporary quarters in Cambridge, which will be my home for about another six weeks. The second half of that period will find the rest of my family in here with me, but for now it's just me, an internet connection, and some take-out souvlaki.

Going to work tomorrow will be a novel experience, after a solid five-month break. But this isn't the first time I've changed jobs, and like everyone else in the industry, I've seen a lot of turnover around me. Both vantage points have suggested some avoidable mistakes when starting a new position.

First off is badmouthing your old company. It's tempting - I mean, after all, you left the place for a reason, right? And isn't the new place so much better, and shouldn't you make everyone happy by telling them so? Actually, no, you probably shouldn't. There's a real risk of coming across as someone who does nothing but moan, and most labs have enough of those folks around already. Keep in mind that you just started, and that people haven't heard you talk much. You don't want your co-workers to realize that half the things you've said so far are complaints. Hold your fire.

You can screw up in the opposite direction, too, of course. (You always can, a general principle I try never to forget). Talking about how things were so much better back at the old gig won't win you any friends either, obviously. Sure, maybe it was easier to order supplies, or get instrument time, or whatever. But no one cares, and you shouldn't either.

This it-was-better stuff turns, very quickly, into another method of complaining, and we're back to the same place as with the first mistake. My view is that grousing about work conditions is something that should be done only among peers that you've worked with for a good while, people who know you and have seen that you can get the job done. At a new job, you don't have anyone in that category yet, so it's better to keep quiet. And anyway, how silly does it look to start in on how things are done when you haven't done anything yet?

Other mistakes: coming on as if you're the answer to everyone's prayers (because that, of course, makes the inference that everyone was doing it wrong until you showed up - if you really are the answer to said prayers, that'll become apparent on its own pretty soon, wouldn't you think)? And its opposite - starting off so quietly that people start to wonder why you were hired in the first place. It's normal (and a good idea) to shut up and listen for a while at first, but that can be taken too far. Eventually, you'll need to speak up.

Well, I won't be making these particular mistakes, I hope, but that just reserves me the right to make some others. At any rate, it's good to get back to research, and no mistake about that.

Comments (13) + TrackBacks (0) | Category: How To Get a Pharma Job | Life in the Drug Labs