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: firstname.lastname@example.org
The realization has gradually crept up on pharmaceutical chemists that the Great Hiring Wave of the last few years is over. For a while there, it was the biggest one ever. It swept in plenty of people fresh out of grad school, and probably decreased the percent of PhDs doing post-docs, since the offers were good whether you did one or not. It also allowed lots of experienced people to jump companies (and here's where I raise my hand, since that's what I did.)
Some history: there last was a noticable hiring phase in the industry in the late 1980s and early 1990s (which, fortunately, is when I was looking for my first job after my own post-doc.) It wasn't anything like what we've just finished, but my impression is that 1986-1991 or so wasn't bad, either. All this came to a screeching halt with the political fights over the Clinton health care proposals. 1993 and 1994 were absolutely terrible years to get a job in the drug industry. Everyone was pulling back and battening down the hatches. 1995 and 1996 returned to somewhat normal levels.
But around 1997, things really began to roll. Several large companies began hiring more aggressively as they expanded their facilities. There was a building boom going on across the industry, and those new labs had to get filled up. Salary offers increased for new hires, and the headhunters began to ring the phones of experienced chemists with some pretty good offers, too (which is what happened to me.) Things kept on hopping for the next two or three years.
I should go back and count ad pages in Chemical and Engineering News to prove this, but I think that last year there was a noticable slowing down. And this year, with all the worries that companies have about their R&D pipelines, there's no doubt about it. My sympathies to those organic chemists who are just finished up degress or post-doc appointments and are ready to hit the interview trail; it's going to be harder (though not impossible.) It's not like 93-94, fortunately. But it's not 1998 any more, either.
A recent view of Jupiter through my telescope made me wonder, as it usually does, just what sort of weird chemicals must be floating around up there. All the ingredients are there, and the intense heat and pressure in the lower layers would be enough to drive most any reaction you could think of. The various colors of the clouds (yellow, brown, red) are a clue that there's plenty going on.
I've seen those colors before, and my organic chemist readers will know exactly where I mean: stuck to the top of the silica columns that I use to purify compounds. Side products in organic chemistry reactions can give you some intensely colored materials, which resemble the colors in Jupiter's clouds quite closely. (Early in his career, Carl Sagan coined the word "thiolins" for these colorful organic mixtures. To a chemist's ear, that makes it sound like sulfur is the most important component, which isn't necessarily true.)
Frankly, though, none of ever really characterize the stuff. We're just trying to get rid of it as fast as possible. Medicinal chemists know that there are mightly few maroon or chocolate-colored wonder drugs; most small organic molecules have no color at all. A few of them are yellow, but a faint yellow color that's usually a sign that you've got a small amount of something that's reallyyellow mixed in there.
OK, there are exceptions, like azulene, a small hydrocarbon which is a startling blue color. It's a useless compound to a medicinal chemist, but I've always been tempted to order some for my lab just so I can have one blue compound in the place. I'm not aware of any organic molecule that's green without the help of a metal like nickel or copper. There are a few honest purples, but they're usually weird anions, nothing that you'd keep around in a bottle.
The corollary to that is that the photos you see of keen-eyed researchers holding up Erlenmeyer flasks of green liquid are faked. It's food coloring. I've been in the lab when they come around for annual-report publicity shots, and they always want to dress things up. The same goes, in spades, for movies and TV shows. If anyone out there has a copy of Ebert's Little Movie Glossaryby Roger Ebert (1994), you'll see my contribution on page 59, the "Law of Colorful Chemicals." (That's not my current address in there, by the way.)
The oddest color I think I've seen was a fluorescent shocking pink compound that turned up in the lab next door when I was an undergraduate. This stuff hurt your eyes; it was dazzling, and completely unexpected. The guy who made it darn near dropped the flask.
There was quite a wave of publicity about a possible "exercise pill" recently. The folks over at Godless Capitalist asked me to take a crack at explaining what all the noise is about. As you might imagine, though, the original research that set this off is a bit less sensational: "Regulation of Mitochondrial Biogenesis in Skeletal Muscle by CaMK" is the catchy title, from a joint effort of teams at Duke and Southwestern/Dallas.
For a long time, it's been known that the key to a muscle's capacity is the number of mitochondria in its cells. Those, of course, are the organelle responsible for energy production. The more you have, the longer you can go without fatigue (which is really just a buildup of toxic waste products formed when the mitochondria can't keep up with demand, and the cell has to switch to other, less efficient pathways.)
It's also been known for decades that exercise causes more mitochondria to be produced inside muscle cells (along with plenty of other changes,) but the genes that are turned on and off to do that are still pretty obscure. One of the things that happens with exercise is elevated calcium levels in the cells, which sets off the activity of several enzymes. These researchers engineered a form of one particular enzyme, CaMK-IV, so that it would be activated even without raised calcium levels. They also took out the section of the protein that would normally keep it inactive under baseline conditions, so the enzyme was set to be set to full activity the entire time.
The transgenic mice made with this mutation are interesting animals. Their pattern of gene expression (and the corresponding levels of various proteins) make their muscles look very similar to normal muscle after extended physical training. Thus the "exercise pill" hype - the mice seem to have developed with pre-exercised muscle tissue.
And, sure enough, microscopic examination showed that the mutant mice had about 50% more mitrochondria in their muscle cells. The teams also identified raised amounts of a protein (PGC-1) that's known to be very important in metabolic balance in fat and muscle tissue. The best guess is that the engineered activity of the CaMK-IV enzyme set off production of more PGC-1, which led to more mitochondria. No one had made that enzyme-PGC connection before - it'll be useful to know that, because PGC-1 has key roles to play in obesity and diabetes, as well as in exercise.
So, now we have a better idea of how muscles figure out how to respond to exercise. Do we have an exercise pill? Nowhere near. Keep in mind that these mice had to be genetically altered to get the activated enzyme. Getting that effect with a drug won't be easy.
One problem is that it's more or less impossible to get an enzyme to do what it does better or more quickly. They're built for speed already. What you can do is find some other system that's naturally slowing it down, and try to gum that pathway up instead, freeing the enzyme of interest to do its thing. (A general motif of medicinal chemistry is that we're a lot better at throwing wrenches into the works than we are at tuning them up to work better; millions of years of evolution are hard to outdo.) There's no guarantee that we'd be able to do this trick with CaMK-IV.
And if we did, there's no telling what might happen (although I'm sure that someone's going to give it a try, and more power to them.) Genetically altered mice, who've had their entire embryonic development to deal with some mutation, can behave very differently from normal adult mice that get suddenly thrown into the same state. A number of these gain-of-function enzyme experiments, for example, have yielded results that don't seem to apply well to the real world (although this one, admittedly, makes a lot of sense.) Don't cash in the health club membership just yet.
It seems that someone got very lucky just before the bad news hit at BMS (see the April 4 posting below.) That's one explanation, and I hope that whoever it was is ready to defend it.
Today's Wall St. Journal reports that the day before the profit warning, some serious option transactions took place in BMS. Ten minutes before the close, orders came in to buy thousands of put contracts, at strike prices of 35 and 40. This was a most unusual spike in volume.
For those who aren't into options, that was a heavy bet that the stock price would fall. Option contracts have a built-in time limit. Each contract gave the holder the right to sell BMS stock at a set price ($35 per share for some of them, $40 per share for the others) at any time before April 20. When those were bought, the stock was at 37, so the right to sell at 40 for the next three weeks is worth at least $3 (the instant profit you could make by buying the stock and selling it at your locked-in price.) In practice, it's worth that $3 plus some extra premium. That extra depends on how long the option's good for and how volatile everyone thinks the stock will be.
Meanwhile, with the stock at 37, the right to sell at 35 isn't worth too much - just the premium based on the chances everything thinks it might have to actually go that low in the time remaining for the option. The only reason you'd buy an "out of the money" option like that is if you expect the stock to drop below 35 in pretty short order. At the very least, even if you don't believe that personally, you must think that a lot of other people are going to believe it, and soon.
Of course, this little transaction (which at its peak value could represent the selling of about 37 million dollars of stock!) paid off very well indeed. BMS promptly closed at about 32 the next day, and has dipped below 30 since. Those options have returned many times their original worth (although it's hard to tell if they're still being held, or held by the original buyers.)
This is the transaction for someone who's not satisfied with a measly 15% overnight profit. They want an overnight 500% to make it worth their while. Accordingly, option trades are one of the first things the exchanges (and the SEC) look at when there's a sudden move in a company's stock. It's like waving a red flag that says "Investigate me!"
I'd hate to have to explain how I got so darned lucky all of a sudden. Good luck to whoever placed these trades. You'll need it when they knock on your door.
That Fitzgerald reference is, of course, the quote about the sign of a first-rate mind being the ability to hold two contradictory statements at the same time. Like several of his other quotes, that one has the germ of spectacular error in it - similar to his line about there being no second acts in American lives. That one gets trotted out with great regularity, as we prove that some lives are made up of nothing but second acts.
Anyway, I'd say that that ability is as often the sign of a third-rate mind or lower. Another example of these contradictions came to mind after I read my mail about the last couple of postings. One correspondent pointed out that we have people watching for every food additive that might be shown to cause cancer, but thanks to Hatch-Waxman we're also letting people swallow almost anything as long as it's labeled as a "nutritional supplement." Some of these are the same people, actually.
Tropical leaves that starving tapirs wouldn't touch, roots whose previous function was to sterilize unwary nematodes, seeds and kernals that would give a buzzard the trots. . .grind it up; it's all fine. You don't really have to test anything for safety, and you don't have to prove it does anything (costs money to do that, anyway.) Just be sure to say that it's "not intended to treat, cure, or affect any disease" and you're rolling.
The latest issue of the fine review journal Trends in Endocrinology and Metabolismhas an article detailing cases where imported traditional "herbal preparations" have turned out to be laced with actual pharmaceuticals. While that reminds me of is the story of W.C. Fields spitting out the contents of his on-set swigging flask, which he always maintained was full of pineapple juice. Someone put him to the test, and his shout was "Who put pineapple juice in my pineapple juice?"
Imagine a traditional preparation of herbal goodies that turns out to be cut with man-made antihistamines or sulfonylureas, rather than Nature's own bounty of alkaloids and cardiac glycosides. Here you are, expecting the usual gut-bomb of all-natural ephedrine, caffeine, or hepatotoxic enzyme inducers, and you get something scraped out of a vat instead. The nerve!
The problem is, it's not just that some fly-by-nighters are slipping pharmaceuticals in. The article also includes harrowing cases of preparations that contained whacking loads of mercury or arsenic, for reasons unknown. Why people swallow the ads for these things, much less swallow the pills, is a mystery to me.
Not much time to post tonight, since our 22-month-old came down with a sudden fever. She's fine otherwise, though, in case anyone's wondering. I'm sure that, as a blog-baby, she'd play well with "Gnat" Lileks.
I've already had several e-mails about my snake-oil outburst in the previous post. No one's come out for the pro-snake-oil position yet; I guess that audience doesn't read me, which is something I can certainly live with.
It was probably the contrast between the ads I mentioned and what I know that medicine can accomplish (see 4/4 and 4/2 postings below.) I've noticed that Sydney Smith over at Medpundit takes issue with both the degree of my gloom and the degree of my optimism. He's got a point about some of the things we can do now (vaccinations are always a good example to adduce,) but I wonder about the popular perception of medical treatment. Large groups of people are worse than I am, in both directions.
There are two mutually exclusive wrong ideas that the general public has about medicine, I think. The first is that there's nothing useful out there, they're just going to mess around with you and waste your time and money, you're going to get what you're going to get, why fight it, etc.
Contrast that weltanschaungwith the second major group: the ones who feel entitled to have everything that goes wrong with them fixed. If one doctor doesn't give them the satisfaction they're after, they go to another. If one medication doesn't cut it, then there's another that will. Generally, there's a sense among this population that any condition can also be traced back to its cause, that person, action, or thing that made them sick. After all, the default setting is perfect health, so something must have happened!
There's a subset of people who manage to believe both of these things at once: these are the big-conspiracy types, who are sure that the doctors and the evil drug companies are ganged up against everyone. (It's an odd viewpoint, when you consider that those two groups - although they need each other - don't always get along very well.) I've had people seriously explain to me that "they" have cures for all these terrible diseases already lined up - "they're" just waiting until everyone's sick enough to make the market really huge.
I give those folks my standard answer to all conspiracy buffs: "Yeah. . .that's what they want you to think. . ."
It's a strongly worded look at the alternative/holistic medicine area, with particular emphasis on the recent attempts to subject these treatments to clinical proof. Many of the practicioners are simply ignoring the studies if they don't give them the answers they want to hear (which, as you can well imagine, they generally don't.)
I can tell you that my blood heats up when I hear the radio ads for potions - excuse me, dietary supplements - to "cleanse your liver" or "sharpen your memory." Not to mention all the miracle weight-loss or hair-growing pills. I feel like I've slipped through some wormhole and ended up in 1910.
Just look at the ancient shucks that are still in business: magnet therapy, iridology, reflexology...you can read all about this stuff in Martin Gardner's first "Fads and Fallacies" book, which is nearly 50 years old. The true and inescapable mark of a pseudoscience is that it doesn't learn a thing. It never changes; the theory is never overthrown; it just keeps on plugging away obliviously. Who cares about facts?
And while I'm on the subject of pedigreed nonsense: if I see another gaudy display of homeopathic dishwater near the checkout of a pharmacy again, I may do something quite reckless. I can only imagine what my medical colleague over at Medpundit thinks about that stuff; I know the herbal supplements really get on his nerves. As they should.
I'll come back later to the subject of the Hatch-Waxman Act, which is one of the things that got us into this fix. For now, check out that article link for a table-pounding good time.
Glenn Reynolds over at Instapundit posted an interesting exchange, which started off as a comment on a post from Kausfiles:
(Mickey) Kaus sees medical advances as inevitably expensive. I think it's more complex han that. Medical expenses actually follow a bell-like curve, like most technology. When you can't do anything, ("here, eat this root and hope for the best") it's cheap. Then you get treatments that are expensive and marginally effective (sanitariums for TB). Then, back on the downslope of the curve, you get treatments that are cheaper and more effective (antibiotics for TB). Cancer treatments now are very expensive. It's entirely possible (I'd say likely) that in 40 years they'll be cheap and much more effective.
UPDATE: Reader Bruce Hay responds: "Yeah, but the cutting-edge treatments will always be expensive. You're right that what's cutting edge today will be tomorrow's familiar (and relatively cheap) treatment. But a new cutting edge will take its place, it will be costly, and every patient will demand it." This is a good point -- though it suggests that the real problem is the appetite for cutting-edge treatments, rather than the movement of the cutting edge. And, actually, there is a natural limit to this progression, which occurs when nearly all physical ills are readily curable. And I think that date may happen within the next 40 years. Or, to be more accurate, people who know a lot more than me, and whose opinions I respect, think that.
Well, as someone from the drug industry, do I think that too? Sometimes I do, actually. But some days I wonder. Both Glenn and his correspondent are correct in their ways. It's true that the latest treatment generally is expensive (since it's usually more complex, and its inventors are trying to make back their discovery costs.) But it's also true that eventually you reach a point where there is no better treatment possible, and then the cost has nowhere to go but down.
A side issue: in a nasty, authoritarian society, you'd expect the opposite: that the treatment's cost would have nowhere to go but up, as the squeeze was applied tighter and tighter to the helpless customers. I know full well that there are people who believe that we live in that sort of society already, but is it necessary to say that I think they're deluded? I despair of convincing anyone with that worldview, because you can't use reason to argue a person out of a position they didn't get into through reason. It's like trying to remove a screw with a claw hammer; it's the wrong tool for the job. But I just don't know what the right tool is in such cases. . .
OK, back to curing everyone. Time for a brief shower of cold water (stick with me, I get more cheerful.) As it stands now, we don't have such wonderful therapies for much of anything, frankly. We've got some good stuff, it's true, but put it up against the ideals and the limitations are clear. There's nothing that makes headaches disappear in seconds or instantly heals a cut, nothing which can quickly and permanently reduce your blood pressure or clean out your arteries. There's no way to really cure almost anything that can go wrong with your liver, pancreas, or kidneys. Sometimes we can stop things from getting any worse. We can fix some cancers (but not many) and those still require some mighty unpleasant therapy. Arthritis? Osteoporosis? Alzheimer's? Parkinson's? We can only treat symptoms, and those rather poorly.
How about infectious diseases? It's a constant struggle, since even the organisms we can actually beat are always coming up with new resistance strategies. Others we can only fight to a vicious standstill, and plenty more are basically stand-back-and-hope. Most viral diseases fall into that category. The viral disease with the absolute widest number of treatment options today is AIDS (which makes sense, but many people don't realize that it's true.) If you're unfortunate enough to come down with viral encephalitis, you'll have to wait it out. If you come down with something like Marburg, you'll die in short order. (Unless you're very lucky indeed. There's a philosophical problem - if you were that lucky, you probably wouldn't have contracted a hemorrhagic fever!)
Well, after that mighty dose of gloom, why do I still think we're going to get all these things sorted out? Because, even though I've spent two paragraphs running modern medicine into the ground, I'm still mindful of the context. Compared with ideal treatments, our treatments are primitive. But compared with the historical standard, they're like having magic powers. Read the opening chapters of Lewis Thomas's "The Youngest Science" for a good perspective on this. A telling quote is from Oliver Wendall Holmes, who said that if the entire pharmacopeia of his time were dumped into the sea, it "would be all the better for mankind, and all the worse for the fish." We're going to make the best therapies of today look just as feeble.
Medical knowledge has been growing insanely fast. My hopes spring from my belief that we're still just in the early lift-off phase of that exponential growth curve. New tools are coming along every year that add to our knowledge at an even faster pace. In a way, we're suffering a bit because of it. I've said before that the pace of pharmaceutical innovation seems to be slowing, but that's partly because we have more clues than we know what to do with. We don't know yet which ones to pursue (or how best to do it.) We'll figure it out, though, because there are vast rewards waiting for those who do it.
In the long run, I fully expect gene therapy and antisense to fix what can be fixed at the genomic level. Downstream, I think we'll eventually get control of protein expression, which should take care of another huge swath of trouble. Small-molecule folks like me (or the next generation after me) will take care of the rest. And as we go after diseases, we'll also be figuring out how to deal with the normal damage of aging. I don't know how long the human life span can be extended, but I'm certain that we don't have to live it in poor health. We may not know the exact mechanism of Alzheimer's, for example, but we know that it's the result of something going wrong, something that can be fixed. Damn it, show me something that can't be fixed!
How long will all this take? I've no idea. But it's coming. Better stand back - or better still, come on down and help out. There's room for everyone, there really is.
>A post of mine from February 26 mentioned in passing the side effects of the anti-HIV protease inhibitor drugs. There's nothing inherent in their mechanism that should cause lipid profile changes and insulin resistance, so the hunt has been on for what other target is responsible.
Now a team at Washington University in St. Louis seems to have picked up the scent. They've found that one of the drugs, Crixivan (indinavir) shuts down the action of a protein called Glut4. Metabolism and endocrinology folks will find that connection pretty believable: Glut4 is one of a family of glucose transporter proteins, whose lot in life it is to take glucose out of the blood stream and pump it into cells. They're found everywhere, with different levels of activity, but Glut4 is key one that responds to insulin stimulation - its action is the primary reason why a shot of insulin lowers blood sugar.
Inhibiting it, then, causes some of the most important actions of insulin to be less effective, which is a back-door route into a state much like Type II diabetes. Lipids and glucose are tied together physiologically, since they're the two main circulating fuels available. You can't mess around with one system without the other responding.
I'm not aware of any other molecules that selectively inhibit Glut4 - as you can imagine, doing that hasn't been a priority for anyone. There's not much of a market for a compound that pushes you toward diabetes. Now, if you knew a way to activatethe transporter, or to keep it working longer, then the metabolic-disease researchers would be ringing your phone pretty quickly. No one's been able to do those things, and many of the steps in Glut4 activation aren't well worked out.
And as far as I can tell, the mechanism by which this new inhibition takes place isn't worked out yet, either. The drugs that cause the side effects are structurally rather different, so the best guess is that they're all hitting some other enzyme that's necessary for Glut4 function. It would just be bad luck that this enzyme, whatever it is, looks enough like HIV protease at the molecular level for drugs to shut down both of them.
If we can find the culprit, then we can try to come up with compounds that are more selective, or find some other treatment to compensate. At the same time, figuring out that problem could shed light on some longstanding problems in diabetes research, too. Stay tuned.