About this site
Here we'll review recent developments in drug discovery and medicine and the IP issues and financial implications they have, along with general thoughts about research. Also likely to make an appearance: occasional digressions into useful topics like which lab reagents smell the worst.
About this author
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.
Step Right Up
We're in or near another bubble-stock period, particularly in biotech stocks. I know I'd have a hard time telling that to companies that are trying to go public right now, but all you have to do is look at the run-ups in some of the small stocks this year. (I can't complain, since I own some, but I don't have to believe in their valuations to profit from them.) The lackluster IPO market makes me think (fear) that we have a lot more bubbling to come, actually.
It's worth going over a few principles of biotech and pharma investing, as seen from an insider's standpoint. For one thing, most of the statements about the research pipelines at such companies are worthless. You really should understand the contempt that researchers have for most Wall Street statements about how their drug projects seem to be coming along. Now, I admit that a lot of that trouble can be traced to the worthlessness of most drug company pronouncements about said projects, but that's another key thing to know, isn't it?
For example, companies keep projects on the books long after they've gone to Drug Development Heaven. At best, they're hoping for something to revive the program somehow, and aren't ready to talk about the problems it's facing. (Sometimes they're not even ready to think about them; self-deception is as big a force in R&D as it is anywhere else.) At worst, they're trying to fake out their competition - and that works, for a while. But when you see something listed as "In Phase I Trials" for, say, three years, you can assume that something has, er, gone astray.
While I'm on the topic of self-deception, remember that it is almost unheard of for a company to undersell a clinical research program. By the time something makes it into advanced clinical trials, plenty of people working on it think that yes, they really are going to get to kick the football this time. And they're as disappointed as anyone else when it gets yanked away, again. I know that there are always those "forward-looking statements" disclaimers at the bottoms of the press releases, but no one reads them. They're background noise. No, you can assume that you are hearing the best possible case that can be made for the drug and for the data. If stock analysts go above and beyond what the company is already dreaming of, they're likely to have entered the realm of complete fantasy.
I realize that these aren't making it any easier to pick good biotech stocks. But hey, we have the devil's own time picking clinical candidates, so why should it be any easier for anyone down the line? And that brings up the root rule of all drug-discovery investing: there are no sure things. Right, it's a truism. But what I mean by that is that there are no sure things, not even close, and you should be appropriately careful of anything that has that glow coming from it.
You are rolling the dice when you invest in this industry. It's interesting, it's fun, it's like nothing else. But we're rolling the dice when we work in it, and you're doing the same when you put money down on us. Never forget it.
Lilly's Psychotic Episode
I'm not actually at work today, but I figured that enough people might be that I should post to give y'all something to read. (Like most blogs, my traffic is highest during the working day, and dips on the weekends.) My reactions are sitting in the freezer at work, where they'll remain until Monday. You can generally count on things not going to hell on you in a minus-twenty freezer, chemically speaking. I did have a key intermediate fall apart in there once in graduate school, to my horror, but that was during a period that made a convincing case for my lab being infested by evil spirits. Having things turn to muck in the freezer was the least of it.
I wanted to mention a bit of news in the CNS field, my old part of the drug world. A head-to-head trial of Eli Lilly's schizophrenia drug, Zyprexa (olanzapine), against the generic standard Haldol (haloperidol) failed to show much (if any) benefit for Lilly's drug. That's really not what you want to hear, of course, about one of your biggest selling drugs. You especially don't want to hear it when your drug costs about 100 times more than the one you tested against.
So how many managed care plans are going to pay for olanzapine now? Lilly had better find some way to show it has some real benefits, assuming that there's actually some way to do that. But it's going to be hard to find some impressive enough to justify that price differential, isn't it?
So, who did this to Lilly? Who ran the study, and (more importantly) who paid for it? It was run with three hundred subjects in the VA system, for one year - not a bad trial at all, for what it was trying to measure. And it was commissioned and paid for by. . .Eli Lilly. Yep, they obviously thought that they'd show a real benefit that would make Zyprexa worth the money. And they struck out, mightily.
And then they let the results be published in the Journal of the American Medical Association, for all the world to see. Keep that in mind when you hear another conspiracy theory about Evil Pharma. We're not angels (I've yet to see an angelic industry.) But we're far from devils - at least, Eli Lilly is. I take my hat off to them.
. . .and no, that stuff about turkey having lots of tryptophan and making you sleepy is a legend. You feel like that because you ate half the darn bird and three slices of pie. Not that I'd know about such things, of course (he says, as he takes his chocolate pecan pie out of the oven.)
At any rate, I hope all my American readers enjoy the day. Those of you in other countries, well, don't expect much out of us over here for another twenty-four hours or so!
The Northern Front
A couple of readers have pointed out that the best candidate for a drug discovered and developed in Canada would be Vioxx, Merck's COX-2 inhibitor. And they're right, that one was discovered in Montreal. Merck's asthma drug, Singulair, gets Montreal credit, too. A good portion of the development work on these two took place in the US, but the Merck Frosst team deserves the credit for them.
We can argue, of course about whether Merck Frosst is really a Canadian company, since Merck bought them back in the 1960s. It's for sure that much of the money that went into this research came from profits made in the US, since that's where the majority of drug company profits are made. (In fact, it would be interesting to compare the total R&D cost for the two drugs to the size of total Canadian pharmaceutical market - I'll see if I can round up the figures.)
But the profits to be made by a hypothetical Canada-only drug company wouldn't justify as much research as Canadian consumers need. It's the money to be made in the US that's driving the whole enterprise. That's partly due to the population differential, certainly, but the situation in Europe is similar. We either need to find a way to do drug discovery more cheaply, which was Peter Lansbury's point in that editorial I spoke about yesterday, or we need to find a way to keep the money flowing in. Preferably both, but we'll take what we can get.
In case anyone's wondering, I'm not saying anything bad about the quality of research that goes on in Canada, or the quality of the researchers doing it. I should know. I work with very capable colleagues from St. John's, Montreal, Toronto, Edmonton, and Vancouver, folks who did their degree work at the best research universities in Canada. And who came here to the US to find research jobs.
Things Only a Friend Can Tell You
Peter Lansbury's op-ed is titled "An Innovative Drug Industry? Well, No." When I see that sort of title, I usually expect the worst sort of pharma-bashing. But, title aside, this is a reasonably even-handed article with some interesting ideas in it. He's missed a key point or two, though, and they're big, ugly ones to have missed.
First off, we can add Lansbury to the list of people who don't buy the industry's arguments on drug reimportation. In fact, he sounds exactly like me:
"The politicians who support reimporting drugs from Canada are sacrificing future medical advances to save money and win votes in the short term. It's disingenuous to claim that reimportation is consistent with a free-market economy, since Canada's lower prices result from government-mandated price controls. Such controls, while lowering the price of existing drugs, would make it impossible for the pharmaceutical industry to engage in the type of innovative research necessary to produce breakthrough medicines. Rather than advance this reasonable argument and call for reform, the pharmaceutical industry, for its part, has raised dubious claims about the safety of Canadian drugs. This transparently self-serving campaign has added to the feeling that the industry is not entirely trustworthy."
He then takes the drug industry to the woodshed about me-too drugs. "Do we really need five indistinguishable versions of Viagra, when they divert resources that could be used to develop innovative drugs for life-threatening disease?" Well, up to a point, he's right. I've written about how not all of these are carbon copies, but some of them are damned close. You do need some sort of distinguishing characteristic or improvement to really make it in the market. Sometimes these are therapeutically valid and useful, but sometimes these are differences that don't make enough of a difference.
Among those Viagroids, for example, Bayer/GSK's Levitra starts working faster, while Lilly/Icos's Cialis works longer. Worthwhile, or not? I've no idea, and it's worth asking, in a broader sense, whether we need three therapies for erectile dysfunction at all. Going over to the statins, this is an even bigger problem with AstraZeneca's Crestor. And there are still worse examples, king of which is Nexium. Not even I can defend that one; I've never even wanted to try.
Now to those innovative therapies we could be developing instead: problem is, there aren't as many wonderful, innovative therapy ideas lying around as we'd all like. It's true that without knockoff drugs, more money could be devoted to chasing after the horde of low-probability ideas that we actually have. But, unfortunately, these days the money we're using to do that stuff comes from those knockoff drugs. It's a more appealing landscape, one in which all the money comes from new drugs that work in new ways, which money is used to produce still more innovations. But I don't know if this is even feasible under current conditions.
To his credit, Lansbury realizes this, and he puts the blame on the legal and regulatory environment that "forces manfacturers to choose between maximizing profits and improving public health." I can agree with the broad philosophy here. I think the way to regulate businesses, any businesses, is to set things up so that they make money by doing the right thing. Remove the worst shortcuts and temptations, then sit back and let the invisible hand get to work.
His first proposal is to find some way to remove patent protection for me-too drugs. That would, I'm afraid, be mighty hard to enforce in its strong form. No matter how you define it, the incentive would be for drug companies to find ways to argue their compounds out of that category. It would just make more work for the lawyers, among others. Lansbury's clearly read the review article I spoke of a couple of weeks ago, about how second and third drugs in a category often end up making more money than the first innovator did. That phenomenon has probably become counterproductive. Perhaps lessening patent protection for later-in-category drugs would strike a better balance. Make it so that there's still money there, but just not as much.
His other idea is a radical one: eliminate Phase III trials. Let companies sell their drugs after a successful Phase II to prove efficacy, under some sort of conditional approval. I think there's merit in this, too, and I'm glad to see that he realizes that the lost me-too revenue needs to be made up somewhere. But yesterday's Merck article here pointed out that Phase III drugs come falling out of the sky, too. They're still not sure things.
This is where Lansbury's academic background shows, I think. He makes no mention of a major thing that would have to happen before we loosen up the regulatory environment: tort reform. I mean, drugs make it all the way through Phase III and onto the market for years before the bad news shows up. And does that slow down the trial lawyers? Hah! They come flapping down, stropping their beaks, cawing about "defective products" and "cash rewards." Can you imagine what these creatures would do to the industry if we ditched Phase III trials? We'd be a pile of bones, bleaching in the sun.
All in all, this is a thoughtful piece, worth a hundred of the usual ill-informed screeds. Lansbury's got a much clearer idea of the way that the industry works. He lives in roughly the same world I do. Well, there is one thing: he states that "The popular image of America's productive and innovative pharmaceutical industry is a historical myth." I'll leave the "myth" part alone for now. Thing is, these days, I just wish that that were the popular image. What's the converse of a straw man? As far as I can tell, the popular image of the pharma industry is of a pack of rapacious ripoff artists, holding on to their top hats as they watch helpless grannies emptying their purses all over the pharmacy counter. And we have ourselves to blame for a lot of it.
The Best. Not Enough.
Merck had some bad news hit last week. Merck, in fact, has been hit by bad news with depressing frequency this year. They've lost an asthma candidate, and their COX-2 inhibitor (Vioxx) has been the subject of safety concerns. Now, in rapid order, two Phase III compounds have crashed on them, which is really disastrous. As far as I know, this leaves them with nothing in their near-term pipeline, except the combination dosage of Zocor and Schering-Plough's Zetia.
Phase III failures are particularly painful. For one thing, you've already spent a huge amount of time and money on the drug. And by that stage, you're starting to count on it. After all, it's made it through human safety trials (Phase I,) and it's shown efficacy against the disease in humans in Phase II.) Phase III is a broader trial based on the Phase II data, to get a better idea of how the drug will peform in real-life situations (outside the rather narrow yes/no of a Phase II.) But by that time, you're sure that it really does work, and you just want to see how well.
Their first wipeout was aprepitant, a compound that's been kicking around in Merck's portfolio for years now, a Substance P antagonist. Substance P is a neurologically active peptide that was first identified in the study of pain (it's a player in the response to capsaicin in hot peppers, for example.) But it has roles in the brain, too, and has been suspected to have roles in anxiety and depression. Merck's tried this compound on all three of them, in basically that order. Negative on pain, and negative on anxiety. Now, after some promise in Phase II, comes a definitive "no" on depression.
Well, depression is a hard trial to run. There's a strong placebo effect; many people feel better just because they think they're taking a drug that might be efficacious. Even the best antidepressants have to be run carefully in large samples before they beat placebos. When Merck broadened their trials of this compound, its beneficial effects disappeared, which could well mean that they were never there in the first place. Perhaps there's a use, somewhere, for a clinically tolerated Substance P antagonist. Merck would love to hear what it is. Right now, the compound is approved to treat nausea in chemotherapy patients, doing about one-fiftieth of what Merck had once hoped for.
Then came last week's news of MK-767's demise. That compound has been in trials for a long time as a diabetes therapy. (It's not from Merck originally - it's a Kyorin compound from Japan, where it was known as KRP-297.) It hits the same pharmacological target (PPAR-gamma) as the known antidiabetics Actos (pioglitazone) and Avandia (rosiglitazone), but adds activity at another related target, PPAR-alpha. The combination has long been suspected to be a potential all-in-one therapy for Type II diabetes, correcting insulin resistance and lipid imbalances simultaneously. A PPAR alpha-gamma compound that worked could easily sell a billion dollars a year, and most of the major drug companies have taken (and are taking) a crack at one.
The Merck/Kyorin compound was well along in Phase III, set to be the first dual-PPAR drug to market, when the roof caved in. Details are sketchy, but it appears that a long-term rodent toxicology test (like three year's worth, damn near the lifetime of most rodents,) showed a "rare malignancy." A lot of people would like to know what it was, but it was clearly bad enough (and compound-related enough) to make Merck halt all clinical development. Novo Nordisk, working with Dr. Reddy's in India, dropped a PPAR alpha-gamma compound a while ago, too, and perhaps there's a connection here.
Or perhaps not. PPAR biology is terrifyingly complex. Despite its importance in two large marketed drugs, there are large, important swaths of PPAR-gamma that are a complete mystery, and the same thing goes, with an extra portion of whipped cream, for the other PPAR subtypes. Different PPAR compounds, which look identical in initial tests, go on to do different things in different tissues for completely divergent reasons. It's been driving everyone insane. I could go on for days of posting about these receptors, from which you might infer that I have an interest in them, but it would pulverize my blog traffic. I'd post some more links, but it's hard to know even where to begin - run the darn things through PubMed and you'll see what I mean. Ideally, you'd want to talk to either GlaxoSmithKline or to Merck about them, because those two companies have been cranking away at basic and applied research in the field for years now.
And it isn't enough. GSK has had PPAR compounds drop out of the clinic, too. So much for the companies that know more about these targets than any other; you can imagine how everyone else feels. Actually, it's the perversity of these targets that's keeping other companies in the game. If the biology were more amenable to talent, time, and money, then the likes of Merck and GSK would have sewn it up with ribbons already.
Well, this all has a bearing on that Lansbury op-ed I keep mentioning, which is here, and tomorrow I'll try to bring things together. But for now, spare a thought for Merck. They have the reputation of doing the fewest me-too drugs in the industry, of not being afraid to spend the money, to take the time to discover something new. And here's their reward. What a business this is.
Ticked Central Station
Time's even shorter tonight than it was last night. Let me point people to this open letter, signed by a passel of economists, coming out against drug reimportation. Here's the real argument against it, laid out for all to see. I wish that my industry would take this and run with it, but we're too busy trying to convince people that they're going to be poisoned if they order their blood pressure medicine from Manitoba. Sheesh.
Thanks to fellow Corantean Arnold Kling for the link. Looking back at his page this evening, I see that we have an intraCorante slugfest going on, set off by Dana Blankenhorn's blast against Tech Central Station. (That's also the site where you'll find that economic open letter, as fate would have it.)
I've had a few pieces published at TCS myself, although I haven't appeared there in a while. Nick Schultz pitched me some more article ideas, but I never followed up on them in a timely fashion. Two of my published pieces were on HIV vaccines, and the third was on a new organic chemistry technique. And I'm at a loss to see how any of them make me, ahem: "a liar, a fraud, a phony who will say and do anything for money." (Blankenhorn's words for TCS contributors.) Y'know, back in the Arkansas of my youth, it probably wouldn't even have helped to smile while you said that sort of thing.
Well, I'll mark his piece as "should have been posted later", which puts it in a fairly large holding tank of the blogosphere. I'm staying out of the fight after this post. I hope.
Worthwhile Canadian Initiative. Right.
There was an op-ed piece in the Washington Post the other day by Harvard's Peter Lansbury that I really want to discuss, but I can't give it the time it deserves tonight. Perhaps tomorrow. (And by the way, it's no wonder that my op-ed submissions to paper like this keep bouncing back, with folks like this sending stuff in at the same time. That, uh, must be it, right?)
Tonight I have just enough time to demolish parts of a remarkably irritating opinion piece from Canadian writer Peter McKnight. This originally appeared in the Los Angeles Times, but has spread back up to Canada, to Newsday, and onward. Didn't Swift say something about falsehood being halfway around the world while truth was still lacing up its shoes?
McKnight is banging away at drug reimportation, and I have to give him his due: he gets in some good shots at the drug industry's attempts to frame this as a safety issue. Readers of this site know that this argument makes my teeth hurt, and I can't blame anyone for not buying it. (As an example, here's a phrase from a recent GlaxoSmithKline press release: "However, encouraging patients to support poorly regulated illegal trade and potentially unsafe business practices - with their attendant health risks - is not the way to resolve the issue of coverage for prescription medicines in the US." A correspondent of mine described this as an insult to his intelligence, and he's absolutely right.
It's such a loser of an argument, not even the likes of Peter McKnight can believe it. And that's saying something, given what he's able to believe. Hey, here comes some of it right now:
"This is a problem of American apathy, not Canadian kindness, toward the underprivileged. But you'd never gather that from the rhetoric of some U.S. poiticians, who say the problem stems from the fact that Canada isn't paying "its fair share."
Let's consider that criticism. Sure, Canadians pay anywhere from 30 per cent to 80 per cent less than Americans for the same drugs, but only because the Canadian pharmaceutical industry agreed to price controls in exchange for increased patent protection. Specifically, the government agreed to extend the length of time before generic versions of patented drugs could come on the market, and the industry agreed to invest more money in research and development. So Canadians are getting what we bargained for and are, therefore, paying our fair share."
Increased patent protection? That's one way of looking at it. What the Canadian government did, starting in 1987, was to actually introduce patent protection. Ever since 1969, Canada had a system of "compulsory licensing," which basically allowed the government to force a drug to become generic. This led to plenty of Canadian generic companies, but not much productivity in the innovative side of their drug industry. The Free Trade Agreement with the US led to a revision of Canadian law, which gave seven years (ten, in some cases) of protection from compulsory licensing. Drugs from Canadian R&D, though, were protected for 20 years.
So that's the source of McKnight's assertion. How has that provision worked out? Just how many of the best-selling drugs in Canada were invented or discovered there? Would you estimate it at, oh, just a ballpark figure of. . .maybe. . .none? "None" sounds about right to me! Anyone have any evidence to the contrary?
McKnight goes on to say:
"The present state of affairs can't continue. And it's up to the U.S. to find a solution because this is an American problem, even though it's causing problems in Canada. Canadian pharmaceutical manufacturers could stop providing drugs to Americans, of course, but that would violate the spirit of free trade, something Americans have championed for years."
Free trade, you say? Artificially capping the prices of drugs that you didn't invent and then selling them back to the people who did is free trade? Here's a counter-suggestion: Canadian pharmaceutical manufacturers could provide Canadians with only the drugs that they've discovered (and paid for) themselves, rather than expected the balance to be made up here. Any takers? You, McKnight? I didn't think so. . .
Synthesis Has Its Uses
I occasionally say unkind things about total synthesis in organic chemistry, so it's only fair that I mention a case when it's actually helped out. There's a large class of natural products which are cyclic peptides, and many of these have interesting biological activities. When they're made up of just the naturally occuring amino acids, it usually isn't too hard to figure out their structure (with modern techniques, anyway - try it forty or fifty years ago, though, and you'd better have had a lot of time on your hands.)
But when they start including the unnatural amino acids, things get a little hairier. There's a class of these peptides called the kahalalides, for example, which have a cyclic part and an amino acid chain stretching off from the ring as well. Some of their amino acids are just weird, and some of them are the normal kind, but mirror-image. You may be able to see some Pacific island roots in that name. The kahalalides are among the many, many natural products that the late Paul Scheuer's group identified at the University of Hawaii. (Back when I was in graduate school, we had a post-doc who came from U of Hawaii. He gave a talk on his grad school research, which included slides of their sailing trip to Fiji where they collected marine sponges to isolate their toxins. We hated him for that, believe me.) These originate with a sea slug, pictures of which can be found on the delightfully monomanic Sea Slug Forum.
Kahalalide F is in human trials as an anticancer compound, so a synthesis of it was worth investigating. (Sydney Smith at Medpundit wrote about this on September 26th.) A group from Barcelona did it, at least according to the structure that Scheuer and co-workers had proposed. Rather to their surprise, though, their freshly made compound had different spectra than the authentic natural product, and turned out to be inactive in cell assays. Something was clearly wrong.
Now the problem has been definitively straightened out. A joint effort from the University of Illinois and a marine natural products company in Madrid has found that two of the amino acids were assigned incorrectly. It's an understandable error - the two are both valines, and they're right next to each other. One's the natural stereochemistry, and one's unnatural, and the original structure assignment had them flipped. The Barcelona group, acting on the suspicion that this had happened, has made this isomer and found that it matches up with the real thing. It's obviously an important region for the peptide to bind to its target.
Getting this one wrong was certainly no disgrace. Kahalalide F's NMR, for example, is no fun at all, unless your tastes run to this sort of thing. There are three more valines in the whole compound, which sure doesn't help in interpreting the spectra, and there are two isoleucines right on top of those, along with some other bits and pieces. Total synthesis was really the only way this pharmacologically important question was going to be settled, but it's a good thing that they had an idea of where the problem was. The molecule has twelve chiral centers, what with all those amino acids. Anyone want to make all four thousand and ninety-six possible isomers, to see which is the right one?
Make Up Your Mind!
(Note: this post has been edited from its original form, since I confusingly said "Phase II" near the end when I meant to say "Phase III." Apologies for all the head-scratching this must have caused.)
It's no wonder that drug discovery is so infuriating sometimes. Seemingly simple questions can be perversely hard to answer. Right now, Pfizer and a partner of theirs, Eyetech, are trying to answer a question that interests them intensely: does Eyetech's drug for macular degeneration work, or not?
Eyetech's compound, Macugen, is from an interesting class of molecules called aptamers, which have been around since about 1990. An aptamer is a single chain of DNA or RNA that selectively binds to a protein. There are already tight-binding, selective protein-protein interactions, of course: antibodies. And the binding and selectivity of single-chain nucleic acid oligomers to their complementary partners are famously unstoppable. Aptamers is an intellectual centaur, an antibody made out of DNA.
Because there are so many neat DNA/RNA tools, aptamers have been the focus of a lot of research over the last decade. You can, in theory, make them pretty easily by producing a big mixture of nucleic acid sequences and seeing if any of them stick to your protein of interest. Then you amplify those and run the cycle again, looking for binding at even lower concentrations. If you like, you can sequence the best of the lot and deliberately make a library of small changes from that template, to focus it down even more. Several cycles of this sort of thing can (and sometimes do) give you an extremely selective, tight-binding aptamer.
But aptamers have been the graveyard of a lot of money over the last decade, too. It's such a neat idea that people tend to think that a lot of the heavy lifting has been done, which is unfortunately not true. As a research tool, they can be wonderful things, but there are no research tools with sales of a billion dollars a year. For that, you want a drug. But as drugs, aptamers suffer from being, well, oligonucleotides. Forget about oral dosing, just worry about if they're even going to work i.v. It's a similar problem to what the antisense people have had, and now the RNAi folks are going through it, too. Oligonucleotides! Here's this incredible spaceship, which can take you anywhere you could want to go. The only problem is, the damn thing is made out of tissue paper and balsa wood.
This one looked more promising than usual. Eyetech's compound is an aptamer that binds to (and inactivates) a vascular growth factor (one of the same targets that many cancer therapies are going after, for the same angiogenic reasons.) Pfizer signed a deal for the compound worth hundreds of millions of dollars, a dreamlike sum for an outfit the size (and age) of Eyetech. Phase II trials of the compound showed some pretty dramatic effects - a quarter of the patients were able to read at least three extra lines on an eye chart. But in the latest Phase III trial, only 6% of the patients had that level of improvement (versus 2% in the control group.) They were able, at least, to show slower declines: 45% of the control group showed a loss of three or more eye-chart lines, as compared to 30% of the drug treatment group.
Unfortunately, I'd be much more inclined to trust the Phase III data. A small trial can lead you astray, because the tendency is to look for patients that are most likely to benefit from your drug. There's a fine line between doing what you can to make a drug succeed, and fooling yourself. Eyetech and Pfizer haven't crossed it, at least not yet, but if the larger trials had broken a bit worse, they might have. It's those larger trials that have more bearing on how a drug will really perform, of course. Once your compound is out there in the market, you don't have much say in what sort of patient uses it. A Phase III trial is supposed to model that and answer more real-world questions.
They're going ahead and submitting the drug to the FDA, though. It does have an effect, after all, just not as much as everyone had hoped. Eyetech should count themselves fortunate, actually Later this week I'll talk about a drug whose Phase III data have made it completely disappear. Now that hurts.
Waiting for the Metaphorical Phone to Ring
This week I should be getting the results from a crucial experiment I set up recently. Actually, the experiment is a whole set of them, a good thirty-two of the little things, and the whole lot has been in a freezer for about ten days now. But they're soon to be thawed out and examined.
And I'm of two minds about that. I've written about this before, the feeling that I think many scientists get of almost not wanting to know if something's worked or not. That's partly because the odds are, for any really interesting experiment, that it hasn't worked out the way you wanted.
Now, there are the exploratory sorts of experiments where anything that comes from them is good. But those don't happen very often, generally only when a field is young and there are observations just waiting to be had. In my business, experiments are generally pass/fail grades on hypotheses. And the risk-to-reward ratio that applies everywhere else in the world applies here: the big experiments, the ones that'll make you jump up and down if they work, generally don't work.
So it really is easier, up to a point, if I don't do things like this. It's not like there isn't enough to keep me busy otherwise - in fact, if I want to do any of these no-guts-no-glory experiments, I have to make sure that I don't get sidetracked by the day-to-day stuff. And it's not like there aren't plenty of highs and lows in what we're pleased to call "normal" drug discovery. It should be enough.
But it isn't, not always. These roll-the-dice ideas keep occuring to me, and some of them just seem to have to be tried out. It's hard dealing with the results, which (so far) have been relentlessly negative. That goes for this current idea, which is a little over a year old, and for the ones I've had in past years. None of the really good ones have worked, not one. And that bothers me, as it would bother anyone. But I think, eventually, it would bother me more if I never tried. Here goes, again.
Let Us Now Praise (Newly) Famous Men
I had some interesting and unexpected news today. My undergraduate Organic Chemistry professor, Dr. Tom Goodwin, has been named as one of four Professors of the Year by the Carnegie Foundation and the Center for the Advancement and Support of Education.
He's the honoree in the Undergraduate category (Hendrix College, my alma mater, has no graduate program.) he's turned out a stream of good students to graduate and medical schools, and we've worked our way into places all over the country. I was his student back in the early 1980s, when he'd only been on the job for a few years, but I've stayed in contact with him and can report that he hasn't gotten any saner since then.
When he was teaching the SN1 and SN2 reaction mechanisms, for example, he put up the standard table of solvolysis rates for the isomeric butyl chlorides. (For those outside the field, they react more and more slowly as they get bulkier, until suddenly, at the bulkiest example, they start reacting more quickly again. The reaction changes mechanism, switching to a completely different mode where lots of bulky branching structure is actually favored.)
Goodwin's method of teaching this was: "As you can see, the rates decrease in the way you'd expect, until you get to this one. It's an outlier, because as it turns out, t-butyl chloride is an abnormally stupid molecule." At that point, at least half the class stopped in the middle of taking notes and started looking at him with a puzzled expression. (A plurality, though, kept on taking notes, which no doubt read ". . .t-butyl. . .v. stupid mol.")
"Yes," Goodwin continued, "science has shown that it has a brain the size of a walnut. Yet it digests tons of hay each day." By that point, even the most clueless had laid down their pens and were staring at him. "Hey," he said, "you teach this stuff year after year, and see what it does to your mind."
He once walked into our lab section wearing a huge vintage gas mask, which certainly got everyone's attention. "Dhoo noht be alahrmhed," he said from inside the thing. "The fhumes haff diffapated. . ." One of the students looked up at the mask and its huge hanging canisters. "What are those things?" she asked. Goodwin peeled it back a bit: "Food for the winter." There are plenty of other stories in the same vein. It would be safe to assume that I took a good deal of my attitude toward my work from the man.
Actually, I was already more or less like this, but Goodwin showed me that you could be that off-kilter and still be a good scientist, which was a relief. It's an attitude that's served me well; I frankly don't see how anyone with a deadly serious personality can do this stuff well at all. So I wanted to take this chance to salute him, and to congratulate him on a well-deserved honor.
Et in Arcadia Ego
I was glad to see that Gregory Hlatky over at A Dog's Life escaped the ax at his chemical company. When the company is cutting back, ou can never be sure that it's not going to happen to you. People get as much insulation around them as they can, with patents, publications, successful projects and so on, and all that helps. But sometimes nothing helps.
You'd think that over here in the drug industry, what with our wild, obscene profits and all, that we'd be immune to these worries. Hah. As I mentioned a couple of weeks ago, Merck has announced thousands of job cuts, and Pfizer's done the same. Bayer, Schering-Plough and others have sharpened their knives this year, too. And if a drug company gets to the point where it starts to cut into research, then things have gotten pretty close, and there's only so much you can do to stay out of the way.
For example, one way to cut the research budget is to drop a whole disease area - one that's costing too much and producing too little. A company will look over its portfolio and say "What have those guys over in Autoimmunity done for us lately? And when are they going to get around to doing something again? And even if they do, how much is it going to cost us to find out if their stuff works, anyhow?" So a whole department gets cut. For chemists, that's pretty bad, but for biologists it's often catastrophic. Chemists are generalists - we do chemistry, and it can be for anything you'd like to to be for. But if the Autoimmune Disease group is going down the chute, then a biologist who specializes in, say, T-cell surface proteins is going to be in bad shape.
I've been in work situations where the rumors circulated every few months. So-and-so was going to buy us. Or merge with us. Or up periscope and fire all bow tubes at us, whatever. It was a different company every time, and none of it ever came true. And another time, I was working away when suddenly an e-mail popped up with a newspaper article saying that the entire research site was going to be closed, and everyone would be fired. That spiced up a slow afternoon, I can tell you.
So we're not immune over here in the Palace of Profit Margins; we never were. I suppose this is all a lead-in to pointing out that tomorrow is Novartis Day in the northeastern US, courtesy of their astonishingly aggressive (and expensive) recruiting campaign. They're having a big hiring symposium at a hotel in Cambridge, and what a mob scene it's likely to be. Tomorrow morning, companies from the Delaware to the Charles are going to be counting the people taking mid-week vacation days, and wondering about what might be going on. . .
To The Editors of the New York Times
Your recent editorial on the Apo-A1 Milano therapy for atherosclerosis is strong stuff. For example, you say that ". . .infusing H.D.L. cholesterol directly into the body, was shown effective in animals more than a decade ago, but the industry never really pursued it. One reason was that companies saw little economic incentive in using a normal body protein for therapeutic purposes, since it would be hard to gain patent protection. A medicine that could be made and sold by anybody had little potential for profit."
There's a lot to argue with here. A "medicine that could be made and sold by anybody" is a good definition of a generic drug, for example, and generic drug companies can actually make plenty of profit. Of course, that only happens after the major R&D costs were incurred by someone else. You came very close to realizing this useful point, but pulled up at the last moment - did you realize that you were about to make an argument for recouping research costs through patent rights?
But the entire piece is an oversimplification, as a little extra thought might have shown. How, by your reasoning, did Eli Lilly ever realize any profit from insulin? It's just another "normal body protein" whose medical use was already known, after all. How did Genentech ever make any money from human growth hormone? We could go on.
HDL therapy has actually had plenty of money thrown at it. You don't seem to have taken the time to find out that human trials of normal Apo-A1 protein for atherosclerosis were attempted several times during the 1990s by at least two biotech companies. They would scarcely have been interested were the financial incentives as low as you picture them. The trials were not conclusive, unfortunately, not least because Apo-A1 is an extremely difficult protein to produce, isolate, or purify. Different preparations of the protein can have completely different qualities - it's a major difficulty in interpreting the scientific literature on the topic.
So you're wrong on that count, too: it cannot be "made and sold by anybody." It's more accurate to say that it can be made and sold by nobody. And I can only imagine the outraged editorial comments your editorial page would have made about rising health care costs if it had come to market. Doubtless you would have favored reimporting it from the cheapest source that could be found.
Moving right along, your understanding of the patent system is also incomplete. Patents are issued for many kinds of inventions. Chemical matter (such as the protein itself) is patentable, as are new or improved methods of producing such materials, as well as new uses for them. A good method for economical large-scale production of Apo-A1 would be a very lucrative patent indeed. In fact, a number of applications and issued patents from the pharmaceutical industry have addressed this exact problem, seeking the potential for profit that you claim does not exist.
Apo-A1 Milano is being pursued not because it is patentable, but because it has already been shown to be remarkably beneficial in the humans who express it. It clearly has very different and desirable properties, compared to the normal protein. As you may recall, this is what caught the attention of the medical research world in the first place. Thanks to the Italian carriers of the gene, key clinical data in humans is already in hand, which is a rare situation indeed in drug development. It's a wonderful opportunity. Now, whether this protein can also be made in sufficient quantities, I don't know. But this topic is, as you may be able to guess by now, the subject of still more patent claims.
So, your editorial bungles its key scientific and legal points. Then you follow that up by lecturing academic and industrial researchers who actually know what they're talking about - here we go: "But the fact that such a promising treatment was widely ignored because there was no immediate profit potential is disturbing. . .This story makes one wonder how many similar gaps exist in the vaunted American research establishment."
Well, speaking as a member of the vaunted American research establishment, I find it irritating to be harangued by the New York Times about a subject you've clearly made little attempt to understand. Spend an hour reading the medical literature before you load up the cannons again - it'll be worth it, trust me. Fill in your own gaps, and then we'll talk.
(For readers who want to take a look at the patents I mentioned, here are some good starting points: Recombinant Apo-A1 production is in US 5643757, and a purification of ApoA and its subsequent uses are claimed in US 5990081. Modified forms of Apo-A1 are claimed in US application 20020156007 and US 6630450, which has an excellent prior art section giving the background in that area. Apo-A1 Milano is covered by US 5876968 and US 6617134. And if any of you guys at the Times use these, let me know so I can bill you for the research.)
Well, I spent most of the day staring at my computer screen at work, putting together a presentation for an upcoming meeting. Since I'd been writing on the subject last night, it's only fitting that most of what I was working on today had to do with molecular and cell biology. After that, my eyeballs can't quite support a decent blogging session tonight!
I had a chance to do a little big more digging for my next screed to the New York Times, which I'll try to post tomorrow night. But the more I look at the Apo-A1 field, the less I believe that patent issues are the main story.
I'll take the opportunity to rearrange the Amazon links below a bit, and put up some new titles. I should put up the oxazole book that I recently wrote a chapter for; I get royalties from that one! I actually got my first check from the publisher the other day - not a huge amount, but it's the first time I've ever gotten a royalty statement. Fascinating reading, they are. Did I mention that oxazoles are the fashionable new heterocycle for the holidays?
Master of None
A couple of items tonight. . .First off, yes I noticed the editorial, aargh, in the New York Timestoday, driving home their point, aargh again, about HDL therapy, the evils of pharmaceutical companies in reference to. As I said on Friday, I'm not sure that I buy their entire theory. I'm working on a letter to them, much good may it do, and I'll post it here as well.
Second, we did indeed get my experiment set up the other day at work, thanks to a colleague in biology. This is the sort of thing that needs collaboration from several departments. When that goes smoothly, it's a great thing. Of course, when it doesn't go smoothly, it's a total abomination, a mighty force for chaos and misunderstanding that can completely wreck a promising research program. If you're running a project, you really, really need to be sure that all your different groups are on speaking terms with each other. Then you need to make sure that they're all using the same words to mean the same things.
In my current experiments, for example, I could learn the techniques for the biological side of things, and do them myself, I suppose. And in the same way, I could learn the fine details of the mass specroscopy techniques that the analytical group will be doing for me this week. But there are, in theory, better uses of my time, and there are better uses of theirs than learning synthetic organic chemistry, too.
That doesn't mean that I can just toss things over to everyone and walk away. A scientist in a large organization has a responsibility to understand what's going on in these other areas. You don't have to get down to the level of where folks keep their buffers, and what brand of 96-well plates everyone likes. But you'd better reach the level of being sure that the right things are being done.
A few years ago, I was involved with the possible hiring of an experienced PhD chemist from another large company. He had been there for some years, and was looking around to see if it was time for a change. The problem was, he didn't know much more than chemistry. After a while, that's a warning sign. After the time this guy had spent, a medicinal chemist should be able to have at least conceptual discussions with the molecular biologists, with the cell culture folks, with the pharmacokinetic people, and with the in vivo groups. This guy couldn't. You see, his company was so huge that he rarely interacted with all those other people. They were all in other hallways of other buildings, and other people were assigned to deal with them on chemistry's behalf. He never had to bother about them, so he never did.
His company had crippled his career. He was quite competent at what he did, but he should have been able to do more. (And, in truth, you had to wonder how much of this lack of growth was his own doing. His company was at fault for making it easy to get pigeonholed, but he was at fault for being a pigeon in the first place!)
Damn Those Patents, Anyway
I've had a chance to go over some of the literature on Apo-A1, HDL, and their therapeutic uses. Before we get going, I'll refer everyone again to the Futurepundit post on the original news, which should get everyone up to speed. There are also some definitions to be handled:
HDL is high-density lipoprotein.
It's actually a conglomeration of several different proteins, lipids, phospholipids and so on. This is the so-called "good cholesterol," because it's the substance involved in taking excess cholesterol back to the liver, where it's broken down or excreted via the bile duct. Apo-A1 is the main protein that's found in the HDL particle.
It's the key player in binding cholesterol and transporting it. HDL particles come in various forms, but one key division is between lipidated and unlipidated forms - that is, carrying a cargo of cholesterol, or empty and ready to be loaded.
Apo-A1 is not a very stable protein. It's tricky to produce or purify reliably, because it's labile to oxidation and loss of some amide residues. It also tends to clump up and self-associate. Overall, being absolutely sure that one prep of Apo-A1 is just the same as another one is a painful and uncertain task. This makes comparison of different experiments pretty tricky, as those in the field are well aware.
The idea of "reverse cholesterol transport" has been around for at least 30 years. Once HDL's function was understood, people began to wonder if extra HDL would be able to scavenge cholesterol out of other tissues. This approach has a big topic in drug development circles for many years now, and all sorts of ideas have been tried to realize it. I'll have more to say on this next week; it's a big topic. I'm quite impressed with the results that the Esperion group has presented. (There's no free link to their JAMA article, unfortunately.) Reducing plaque size by that amount in such a short period is a real achievement. It's about as convincing an argument for RCT as you could ask for.
But the press coverage has stressed something that Gina Kolata's article for the New York Times brought up (see the Futurepundit link above to see how it catches a person's eye.) Kolata states that the only reason that Esperion is working with the Milan protein is that it can be patented, whereas naturally occurring HDL can't be. This is at best an oversimplification, and at worst it's a flat distortion of the facts.
Here's why. What doesn't get mentioned is the history of HDL therapy. The idea of infusing artificially produced or reconstituted HDL was first proposed in 1984. Over the last ten years, plenty of evidence in animal models has been generated to back up this idea. These have included making transgenic animals express more (or less) HDL, transplanting arterial tissue between different strains and watching the effects, making and injecting HDL, Apo-A1, or some smaller protein that keeps its key cholesterol-binding structure. Many of these studies have been promising, but there have been some dead ends due to the different way animals handle cholesterol and other lipids. It's certainly kept everyone busy.
In 1995 and 1996, two groups reported human trial of lipid-free Apo-A1 and various mixtures of Apo-A1 and phosphotidylcholine. Results were mixed, but some of the treatments seemed to promote cholesterol efflux, as hoped. Others did very little. Comparing the results is difficult, because of different formulations and dosing regimens, and the above-mentioned difficulty in knowing if everyone was even using the same form of the protein.
Folks kept at it. In 1999, a Swedish group showed that administering the protein percursor to Apo-A1 was a good method to clear cholesterol from human volunteers, both normal subjects and those with a family history of high cholesterol. The same group reported further data last year, but pointed out that "The concept of infusing reconstituted HDL as a therapeutic alternative is still far from practical reality." They pointed out that the protein was extremely costly and hard to purify, that there could be immune problems with long treatment, and that long clinical studies would be needed to see what the real effect on human disease might be.
Now we finally get to the Milan mutation. Back in the late 1700s, the founder of this line was born with a random mutation in his Apo-A1. One arginine amino acid was replaced by a cysteine, and this had some profound effects. There are 40 or 50 descendents alive today in northern Italy, and they show a strong tendency toward protection from coronary heart disease. Their mutant Apo-A1 seems to have a longer lifetime in the plasma, and also seems to be more efficient at scavenging cholesterol. These improved properties, and the fact that this protein had already been "pre-tested" in humans, were as important as any patent considerations.
Note also that the natural, presumably unpatentable, form of Apo-A1 has been tweaked and modified quite a bit in its clinical studies. There are, I should think, eminently patentable processes there. Anyone, for example, who found a way to get around the purification difficulties of the native protein would patent the method immediately, and they'd get it, too. Any nonobvious formulations or dosing methods would be patentable - just find one that works. And I haven't even mentioned all the peptide analogs that people have been making - patentable, every one of 'em.
No, I think that the main advantage of the Milan mutation could be that it simply works better. I don't know how much easier it is to purify, but it seems worth going after just for those reasons and the evidence from the Italian patients themselves. Esperion has a long way to go with this stuff, and they'll deserve to make the money if they can get to the end of their efforts. Even Gina Kolata might be a customer.
Note: if anyone wants the references to the work I've cited, see the review articles in Atherosclerosis, Supplements 3 (2002), 31 and J. Pharm. Pharmacol. (2000) 52, 731.
HDL and More
No time to do decent blogging tonight. Tomorrow night I hope to post something about the Apo-A1 (HDL) news that everyone's been talking about. It's a very interesting result, potentially of great importance for treating atherosclerosis. Randall Parker over at Futurepundit is right on target when he speculates that things like this are likely early candidates for "better than normal" gene therapy, once that finally gets going. If you could tweak a few amino acids to make yourself (or your progeny) nearly immune to arterial plaques, wouldn't you? (His article, by the way, is an excellent summary of the whole Milano Apo-A1 story - reading it will save me the trouble of recapping!)
The aspect that keeps getting stressed in this story, though, is the New York Times angle that patent rights are the only reason this mutated protein is being worked on. I'm looking into that claim to see how it holds up. It seems to me that there would be a number of potential patent claims you could make using regular HDL, so I'm not completely sure that I buy this argument. Time for a look through the patent literature. . .
More on this when I have time to give it the attention it deserves. I have a sick kid this evening, and my local medical needs are taking priority. Meanwhile at work, tomorrow marks a crucial experiment in a long-running idea that I've been working on. Hardy Lagniappe readers will recall me talking about this during the summer and fall of 2002, and I'm still at it. This could be a good one, but I won't know the results until early next week, when the analytical chemistry group has time in their schedule to check it out for me. I've waited this long; a few more days won't do me too much harm. I think.
Fill It to the Rim - With Brimstone!
Today's Wall Street Journal had an impressive photo of a gigantic pile of sulfur heaped up in Alberta. It's been extracted from high-sulfur crude oil, and it's got to go somewhere. I'm sure the Albertans would rather sell it to someone, but there's so much of it around that the cost of shipping wipes out any potential profit. Sulfur's a glut on the market - there's a similar ziggarut of the stuff in Russia, for example.
Update: I e-mailed Colby Cosh to ask him if he'd seen this thing, and he replied that "it depends on which gigantic pile of sulfur you're talking about." He has the links to prove it, too!
We're not going to be able to help them out very much in the drug industry. Some highly oxidized sulfur compounds are fine by us - sulfonamides, for example, because they're rock-solid-stable and easy to make. Sulfones are OK, too, but you can't crank them out by the score like sulfonamides. But sulfonic acids have never been all that much use to us as drugs; they're too polar and don't get into cells very well. The intermediate sulfonyl chlorides are just too reactive - I've never seen anyone desperate enough to propose one as a pharmaceutical.
(Although for reactive substances, sulfonyl chlorides sure take their time breaking down. If you spill a bunch of tosyl chloride, the most often-used sulfonyl chloride, the smell hangs around forever, no matter how damp the conditions are. And yes, I know this from experience. In graduate school, I had a synthetic step that required really clean tosyl chloride, which I had to recrystallize. The postdoc whose procedure I used had written down his technique, and the part I recall best was "filter the crystals, add more hexane to the filtrate and cool to get a second crop. Treat that filtrate the same way, and go on until you get no more crystals or until you just can't take it any more." The second stage invariably came first.)
Sulfoxides, the next oxidation state down, get some use. We do go through some DMSO as solvent, although the stuff is a bear to get rid of, since it has the approximate boiling point of pancake syrup. One of the best compounds I ever made was a sulfoxide. actually. That one, through stock options granted to me for its synthesis, eventually turned into the down payment on my house, so you'll never hear me say a bad word about 'em. But they have their detractors, since they're sort of poised between falling up to sulfones or down to sulfides.
And when you get to sulfides, trouble starts. They're just oxidized too easily, and it's rare that one is seriously advanced as a drug candidate (and when one is, the sulfide is usually the first thing that's chewed up.) But they're just upstanding citizens next to thiols, SH compounds. The early ACE inhibitors were thiols, so it certainly is possible to make a drug out of one. But who wants to? They turn into disulfides if you look at them funny, and they tend to reek to the skies if they have any vapor pressure at all. I'll do a whole post sometime on their nauseating properties, because they deserve space all their own. You won't want to miss that one, I'm sure.
About other low-valent sulfur compounds, the less said, the better. I had a flask full of a sulfenyl chloride blow up on me while I was holding the damn thing in my hand once. I went straight up in the air, shouting obscenities, and was back on the ground for a few seconds before I got up the nerve to look down and take inventory of my fingers. Never again.
Nope, I have no good news to offer the sulfurous Albertans. The suggestion they've had to turn their yellow mountain into a tourist attraction is probably their best shot!
Give It Up!
I haven't commented on the fuss over the Physiology/Medicine Nobel this year, but a couple of developments today lead me to it. As most readers will know, the prize was given to Paul Lauterbur and Sir Peter Mansfield for their work in NMR imaging as a medical technique. I don't think anyone can deny that they deserve it, but there's another person with a plausible claim.
That would be Dr. Raymond Damadian. I won't go into the tangled history of medical NMR (it's available here), but he is clearly one of the inventors of a basic idea behind MRI: that many tumors had reproducibly different NMR behavior than normal tissue. He's been recognized as such before, and many people familiar with the field were surprised when his name wasn't on the Nobel citation.
However, the Nobel committee is under no compulsion to award the prize to everyone that has a hand in a discovery - they're free to pick and choose. In this case, they seem to believe that Damadian's work, though groundbreaking, was not as important in the later development of the imaging technique. That's a reasonable argument - Damadian's discovery wasn't well adapted for that. If the prize was supposed to be for the use of NMR on living tissue, he'd have a right to expect to be on it. If the award is for NMR imaging as a medical tool, his case isn't quite as strong. And that's how the Nobel citation to Lauterbur and Mansfield reads: "for their discoveries concerning magnetic resonance imaging." The wording is surely deliberate.
So many other people familiar with the field weren't surprised one bit when Damadian was left off, and they were able to read between the lines quickly. Damadian is, well, a difficult person to deal with. His unconcealed contempt for Lautenburg has caused trouble on more than one occasion. Actually, concealing any of his feelings isn't his strong point. As he told Chemical and Engineering News (in its latest issue), "I'm a very, very, very, very sore loser." (Revealingly, that's how they quoted him, and in a bold-faced pull quote, yet.)
That article is one of the things that prompts to to write. Damadian seems to be even more of a short-fuse artist than I'd heard. C&E News also quotes him as saying "There's a band of buccaneers in Stockholm that has been victimizing people for a century with their crimes." That would be the Nobel committee, in case you're wondering. Another thing you might be wondering about is just how Damadian thinks that he's going to get anywhere with them, spouting off like that.
But you know, in a way, he's right. It really doesn't matter what he says, or how he says it. The Nobel folks are just not going to change their mind. They never have, and have stated repeatedly that they're not going to start now. (And I see their point - wouldn't that just open the floodgates!) It's a lost cause; it's been lost from the beginning. But that hasn't stopped Damadian from taking out full-page ads in US and Swedish newspapers, ranting about how he's been wronged.
The latest one came out this week. They've been getting longer and weirder, and the latest one is the other thing that got me to write about this whole affair. Its verbose thrust is that Lauterbur and Mansfield aren't even M.D.s, for crying out loud, and won't all the doctors of the world get together, help one of their own, and make the Nobel committee see some sense?
Yeah, I'm sure they'll get right on that. Damadian hasn't noticed, I suppose, that the science prizes have a lot of wiggle room in them (this year's chemistry prize was about as biological as it comes, for example, and some years it's pretty pure physics.) Or if he's noticed, he just doesn't care.
Well, he can save his money (those ads aren't cheap!) and his breath. None of this will do any good; it's long since switched over to doing harm. The louder he shouts, the more he tarnishes his name, unfortunately. As C&E News puts it, "He may find himself remembered more for complaining about the Nobel Prize than for inventing MRI." It seems a rather degrading sort of immortality.
After I wrote about what kinds of med-chem projects to seek out (and what kinds to avoid,) one of my colleagues asked me about taking over a project that someone else started. Did that situation have any special features?
It does, but they depend on what kind of job your predecessor was doing. If things were going fine, then - sad but true - you will get no credit for successfully delivering a clinical candidate. You'll just be seen as the person who didn't mess things up. There are worse reputations to have, for sure, but there's little way to get any real credit in a case like this.
And there's plenty of room to get some real blame. If things only appeared to be going fine, then you've been handed a bag of snakes. It falls to you to bring everyone back to reality, and no one's going to enjoy it. There's a real risk that you're going to be seen as the person who made all the trouble, rather than as the person who fixed it. It's a delicate, sometimes insoluble problem.
The only way you can reliably come out well by taking over someone's work is if things weren't going smoothly. Then it's up to you to fix it, with credit if you do, and a ready-made reason if you don't. I'd rather be in this position than than the other. Actually, I'd rather not take over a project from someone else in the first place. But at many companies, that's the standard procedure, so you need to learn how to deal with it.
Now, all this may sound a bit calculating and cynical. But I've concluded that it's necessary to make those calculations. Appearance isn't enough to get you by, not in the long run. But it is enough to sink you, no matter how much substance you really have. Judging talent, particularly scientific talent, is a very inexact process, and you can't expect your peers and superiors to be experts at it (since not many people are!) Avoiding situations where you have a high chance of looking bad, then, is only prudent.
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