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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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August 30, 2013

Totally Off Topic: My Appearance on Jeopardy!

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Posted by Derek

I've had several requests for details about the time I was a Jeopardy! contestant, since I mentioned it in passing the other day. So for the holiday weekend, I thought I'd provide the story. This was all back in 1995-1996, when I lived in New Jersey, and that's actually how I got into the entire business. Coworkers had told me about how the Merv Griffin production people would be administering the test to get on the show down at the Resort International casino in Atlantic City (also owned by the Griffin company), so I drove down to try it out.

The test was only a short one, meant to be done quickly as a screen, and none of the questions seemed particularly hard. I spent the rest of my time in AC working on my card-counting skills at the blackjack table, which was not too lucrative. In fact, under the rules then - and I'm sure they've gotten no better - the same amount of time and effort applied to almost any other activity would surely have provided a greater return. (But at least they couldn't throw you out, as opposed to Las Vegas).

Not too many days later I got the invite to come down for the longer test, which had many more questions, all of which, I think, were from the $1000 category on the show. This was at the same casino, and I knew that morning, on the drive down, that I was in trouble. I'd gotten a late start, it was rainy, and there was more traffic than I'd counted on. I pulled in a few minutes late, bounded up the escalators, and was met by a lady sitting at a long table in front of a closed door. "I'm sorry", she said, "the test has already started".

"But there's another one in a couple of hours", she said, to my surprise and relief, "so we'll just put you down for that". Just then, there was the sound of someone frantically taking the escalator steps two at a time. Into view came a guy who looked even more frantic than I had - shoes untied, shirt half tucked in, hair sticking up on one side. "Don't worry!" I called. "There's another test later!" He caught his breath while taking in this news, and it was then that I noticed that his hands were full of almanacs and trivia books and the like. We walked off together, and he said "Good, good. . .this will give me time to study up some more!"

"I'm pretty much done with it", I told him. I had been brushing up over the last week on things that I didn't have covered so well - opera, Academy Award winners, some sports records and American presidential trivia - but I wasn't lying to him at all. I figured that if I didn't know something by the day of the test, I was unlikely to remember it when I needed to. "No, I've got to read up on things," the guy said, then turned to me and said "For example, what's the capital of Uzbekistan?"

"Tashkent", I told him, with no hesitation. Science, literature, history, and geography were my strong areas. He looked startled. "Oh s$%&!" he said, and sped off for parts unknown, there to clarify his map of Central Asia. After lunch it was time to take the test (much more challenging), and to wait around while the staff graded our sheets. They then called everyone together and read off the names of the people who had passed. Mister Tashkent did not seem to be among them, and I wondered if I'd fatally psyched him out. We did some dry runs of the game at that point, which served (from what I could see) to weed out the people who kept going "Ah. . .ah. . .um. . ." whenever it came time to answer a question.

And that was that, for a few months. They'd told us that we were on the list as possible contestants, and there was no way of knowing when or if we'd be called. But one day I had a message from LA, with the day of a taping, and I flew out for it quite happily. (I should note that the show covered not one penny of expenses, at least for the regular daily contestants). I showed up at the studio nervous but ready to go.

I got to see a couple of shows taped with some of the other crop of contestants before my turn came, and that gave me a chance to see some of the workings. The key to the whole thing was the moment of picking and answering. You had a chance to read the clue off the monitor while Alex Trebek was reading it out loud, and that was the time to figure out if you knew it and to prepare to try to answer it in the form of a flippin' question. You could not press your contestant's button too early, though - as they explained in detail, that locked you out for a delay period if you tried it, which would almost surely leave you without a shot. Timing was crucial. You had to wait for Trebek to stop speaking, wait about a sixteenth note of time, and then hit your button.

With the other two guys in my taping, that generally meant that all of us sat there poised while Trebek read off an answer, and then suddenly clickityclickityclickclick we'd all hit the buttons, so close to simultaneously as seemed to make no difference. There were a few times that I knew I'd reached out and snatched the right to answer a question, but others where I thought I had (but hadn't), along with a couple where I was as surprised as anyone else when my light came on.

It all happened very quickly, and took a lot of concentration and fast thinking. The effort of reading answers and coming with questions, while simultaneously watching the timing, deciding which category to go for, and keeping up with the score of the game was plenty to deal with. I remember two parts of the game very clearly, though. At one point, the taping paused for the commercial break, and some staff members came out to reapply makeup. I needed quite a bit, and Trebek remarked to the guy "You don't spend that much time on my makeup". "You don't sweat this much, Alex" came the response.

The other part I recall clearly was the Daily Double, which I was actively prospecting for whenever I had control of the board in the second round. I'd lost out on a few questions, and needed it to get back in the game. To my happiness, it came up in Geography, and I bet most of what I could. Up came the answer: "Lake Nasser sits on the border of these two African countries". My brain immediately pictured a map, while I played for time. Nasser could only mean Egypt, but I was having trouble figuring out the second country. "What are Egypt and. . . ." I started, while thinking to myself that it couldn't be Libya, that was a total desert out there. . .and the other side of the country, that was a coastline, the Red Sea. Trebek was looking at me, eyebrows raising a bit in anticipation, as if to say "You're not going to blow this one, are you?", as I finished with ". . .Sudan!". He gave a quick smile, and we were off again.

By the end of the game, I was in second place by $200 or so, a close race. The final Jeopardy category was English Literature, which gave me great happiness. The clue was "Mellors is the gamekeeper in this novel", and I immediately wrote "Lady Chatterly's Lover" on the scraggly, time-delayed screen. My only hope was that the guy ahead of me didn't get it, but alas, we all did. I lost, $13,300 to $13,100. The sensation was exactly that of coming off a carnival ride; the first thing I wanted was to go around again.

What valuable prizes did I win? Furniture, which I decided later to decline. I believe that a lot of it gets turned down like this, and probably for similar reasons to mine. I didn't care for the style, and had no place to put it. I could have perhaps sold it to someone, but this was pre-Craigslist, and in the meantime I was going to be paying tax on the full retail value, both to the IRS and to the state of California (a state tax form had been included in my going-away packet). A couple of weeks after I got back home, a package showed up with some boxes of Miracle-Gro, various flavors of cough drops, and other "Some contestants may also receive. . ." items (but alas, no Rice-a-Roni, which my family never ate while I was growing up, and which I always associated solely with game shows).

So that was my Jeopardy! experience. I enjoyed it tremendously, and I told people when I got back that I would have liked to be a contestant on the show for a living. A diet of Miracle-Gro and cough drops might have eventually impaired my button-pressing response times, though.

Comments (22) + TrackBacks (0) | Category: Blog Housekeeping

Welcome to the Author's Brain. The "Fasten Seatbelts" Sign Is Illuminated

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Posted by Derek

Well, it's the Friday before a long holiday weekend here in the US, so I don't know if this is the day for long, detailed posts. I do have some oddities in the queue, though, so this is probably a good day to clear them out.

For starters, here's one in the tradition of the (in)famous Andrulis "gyre" paper. Another open-access publisher (SAGE) has an unusual item in their journal Qualitative Inquiry. (Some title, by the way - you could guess for days about what might appear under that category). The paper's title gets things off to a fine start: "Welcome to My Brain". And the abstract? Glad you asked:

This is about developing recursive, intrinsic, self-reflexive as de-and/or resubjective always evolving living research designs. It is about learning and memory cognition and experiment poetic/creative pedagogical science establishing a view of students ultimately me as subjects of will (not) gaining from disorder and noise: Antifragile and antifragility and pedagogy as movements in/through place/space. Further, it is about postconceptual hyperbolic word creation thus a view of using language for thinking not primarily for communication. It is brain research with a twist and becoming, ultimately valuation of knowledges processes: Becoming with data again and again and self-writing theory. I use knitting the Möbius strip and other art/math hyperbolic knitted and crocheted objects to illustrate nonbinary . . . perhaps. Generally; this is about asking how-questions more than what-questions.

Right. That's word-for-word, by the way, even though it reads as if parts of speech have been excised. Now, I do not, sadly, have access to journals with the kind of reach that Qualitative Inquiry displays, so I have not attempted to read the whole text. But the abstract sounds either like a very elaborate (and unenlightening) word game, or the product of a disturbed mind. The Neurobonkers blog, though, has some more, and it definitely points toward the latter:

This article is therefore about developing recursive intrinsic self-reflexive as de- and/or resubjective always evolving living research designs. Inquiry perhaps full stop—me: An auto-brain—biography and/or a brain theo­rizing itself; me theorizing my brain. It is thus about theo­rizing bodily here brain and transcorporeal materialities, in ways that neither push us back into any traps of biological determinism or cultural essentialism, nor make us leave bodily matter and biologies behind.

Apprarently, most of the manuscript is taken up with those "This is about. . ." constructions, which doesn't make for easy reading, either. At various points, a being/character called "John" makes appearances, as do recurring references to knitting and to Möbius strips. Brace yourselves:

Knitting John, John knitting. Knitting John Möbius. Möbius knitting John. Giant Möbius Strips have been used as conveyor belts (to make them last longer, since “each side” gets the same amount of wear) and as continuous-loop recording tapes (to double the playing time). In the 1960’s Möbius Strips were used in the design of versatile electronic resistors. Freestyle skiers have named one of their acrobatic stunts the Möbius Flip. The wear and tear of my efforts. My stunts, enthusiasm knitting. My brain and doubling and John.

OK, that's deranged. And how could anyone at SAGE have possibly reviewed it? This is the same question that came up with the MDPI journals and the Andrulis paper - five minutes with this stuff and you feel like calling up the author and telling them to adjust their dosages (or perhaps like adjusting yours). This sort of thing is interesting in a roadside-accident sort of way, but it also calls open-access publishing into disrepute. Maybe it's time for not only a list of predatory publishers, but a list of nonpredatory ones that freely admit garbage.

Comments (43) + TrackBacks (0) | Category: The Scientific Literature

August 29, 2013

A New Pathway For Memory

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Posted by Derek

As someone who will not be seeing the age of 50 again, I find a good deal of hope in a study out this week from Eric Kandel and co-workers at Columbia. In Science Translational Medicine, they report results from a gene expression study in human brain samples. Looking at the dentate gyrus region of the hippocampus, long known to be crucial in memory formation and retrieval, they found several proteins to have differential expression in younger tissue samples versus older ones. Both sets were from otherwise healthy individuals - no Alzheimer's, for example.

RbAp48 (also known as RBBP4 and NURF55), a protein involved in histone deacetylation and chromatin remodeling, stood out in particular. It was markedly decreased in the samples from older patients, and the same pattern was seen for the homologous mouse protein. Going into mice as a model system, the paper shows that knocking down the protein in younger mice causes them to show memory problems similar to elderly ones (object recognition tests and the good old Morris water maze), while overexpressing it in the older animals brings their performance back to the younger levels. Overall, it's a pretty convincing piece of work.

It should set off a lot of study of the pathways the protein's involved in. My hope is that there's a small-molecule opportunity in there, but it's too early to say. Since it's involved with histone coding, it could well be that this protein has downstream effects on the expression of others that turn out to be crucial players (but whose absolute expression levels weren't changed enough to be picked up in the primary study). Trying to find out what RbAp48 is doing will keep everyone busy, as will the question of how (and/or why) it declines with age. Right now, I think the whole area is wide open.

It is good to hear, though, that age-related memory problems may not be inevitable, and may well be reversible. My own memory seems to be doing well - everyone who knows me well seems convinced that my brain is stuffed full of junk, which detritus gets dragged out into the sunlight with alarming frequency and speed. But, like anyone else, I do get stuck on odd bits of knowledge that I think I should be able to call up quickly, but can't. I wonder if I'm as quick as I was when I was on Jeopardy almost twenty years ago, for example?

(If you don't have access to the journal, here's the news writeup from Science, and here's Sharon Begley at Bloomberg).

Comments (7) + TrackBacks (0) | Category: Aging and Lifespan | The Central Nervous System

How Goes the War?

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Posted by Derek

There's an article at The Atlantic titled "More Money Won't Win the War on Cancer". I agree with the title, although it's worth remembering that lack of money will certainly lose it. Money, in basic research, is very much in the "necessary but not sufficient" category.

The article itself is making the case of a book by Clifton Leaf, The Truth in Small Doses, a project that started with this article in Fortune in 2004. Here's the pitch:

What if a lack of research funding isn’t really the problem? One reason we aren’t making faster progress against cancer, according to Leaf, is because the federal grant process often chases the brightest minds from academic labs, and for those who do stay, favors low-risk “little questions” over swinging for the fences.

“More money by itself is not going to solve anything,” Leaf said. “Let’s say we doubled the [National Institutes of Health] budget, that isn’t going to make the lives of researchers better.”

The problem, as Leaf sees it, is with the business of cancer research. Over the last decade or so, “doing science” has reached a crisis stage—a claim many in the cancer community agree with, even if they don’t quite see eye-to-eye with Leaf on all of his conclusions.

His take is that the grant-money situation is making academic researchers spend more and more time just trying to get (or stay) funded, and that they tend to avoid anything that might sound a bit unusual in their applications. He also fears that academic researchers are taking too long to get established, that what might be some of their more creative years are being wasted in lengthy post-docs and struggles for tenure. I think that these are real problems, although they've been coming on for a long time now.

The article seems a bit too focused on the academic side of things; I don't know yet if the book makes the same mistake. Looking at it from industry, I think that the odds are that the first fundamental insights are more likely to come from academia, but I also think that the heavy lifting of turning these into real treatments will be done by industry. The difference between these has come up many times on this site, but it's safe to say that the general public does not appreciate it. The only place a breakthrough in the lab means an instant breakthrough in the clinic is in the movies.

To the extent, though, that people are told that "More Money" is the answer in this field, I think it's good to make the point that it isn't necessarily the limiting factor. Problem is, there's no way to hold a charity insight-raiser, or to set up a box to Donate Good Ideas For the Cure. Medical research, whether industrial or academic, is a pretty esoteric field to most people. There's not much way for an interested lay person to help out directly; the technical background is too much of a barrier. So people raise money, (while some just raise "awareness", a particularly slippery term), because it's the only way that they feel that they can make any difference.

Also, as has been said many times before, the "war on cancer" term is an unfortunate one, because it makes it sound as if there's a single enemy to be defeated. What we have is a war on our own ignorance of biology and medicinal chemistry, and that's going to be a long one. But perhaps I'm making the mistake that oncology pioneer Sidney Farber warned about:

(The patients) with cancer who are going to die this year cannot wait; nor is it necessary, in order to make great progress in the cure for cancer, for us to have the full solution of all the problems of basic research…the history of Medicine is replete with examples of cures obtained years, decades, and even centuries before the mechanism of action was understood for these cures"

Problem is, the only way I can think of to come up with cures without such understanding is to do a lot of out-there clinical trials, at high risk. Farber himself took that approach, famously, and managed to win out. But I'm not sure what appetite we'd have for it on a broad scale.

By the way, if you take a look at the comments section to the Atlantic piece, you'll find the usual stuff. You know - the drug companies don't want to cure cancer, no way. If people would just follow Doctor So-And-So's Miracle Diet, they'd be fine. According to these folks, all this talk of cancer research is a sham to start with. Of course, the number of such "cures" is beyond counting, and since so many of them claim to cure most everything, you'd think that they can't all be right. But somehow this doesn't seem to faze their adherents, who are often enthusiasts for several broad miracle cures simultaneously.

Comments (33) + TrackBacks (0) | Category: Cancer

August 28, 2013

Mercury Azides. I'll Get Right On Those For You.

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Posted by Derek

Azides have featured several times in the Things I Won't Work With series, starting with simple little things like, say, fluorine azide and going up to all kinds of ridiculous, gibbering, nitrogen-stuffed detonation bait. But for simplicity, it's hard to beat a good old metal azide compound, although if you're foolhardy enough to actually beat one of them it'll simply blow you up.

There's a new paper in Angewandte Chemie that illustrates this point in great detail. It provides the world with the preparation of all kinds of mercury azides, and any decent chemist will be wincing already. In general, the bigger and fluffier the metal counterions, the worse off you are with the explosive salts (perchlorates, fulminates, and the others in the sweaty-eyebrows category). Lithium perchlorate, for example, is no particular problem. Sodium azide can be scooped out with a spatula. Something like copper perchlorate, though, would be cause for grave concern, and a phrase like "mercury azide" is the last thing you want to hear, and it just might be the last thing you do.

As fate would have it, though, none of this chemistry is simple. You can get several crystalline forms of mercuric azide, for one thing. The paper tells you how to make small crystals of the alpha form, which is not too bad, as long as you keep it moist and in the dark, and never, ever, do anything with it. You can make larger crystals, too, by a different procedure, but heed the authors when they say: "This procedure is only recommended on a small scale, since crystalline α-Hg(N3)2 is very sensitive to impact and friction even if it is wet. Heavy detonations occur frequently if crystalline α-Hg(N3)2 is handled in dry state".

Ah, but now we come to the beta form. This, by contrast, is the unstable kind of mercury azide, as opposed to that spackle we were just discussing. These crystals are not as laid-back, and tend to blow up even if they're handled wet. Or even if they're not handled at all. Here, see if you've ever seen an experimental procedure quite like this one:

After a few minutes, the deposition of needle-like crystals starts at the interface between the nitrate and the azide layer (β-Hg(N3)2). After some time,
larger crystals tend to sink down, during this period explosions frequently occur which leads to a mixing of the layers, resulting in the acceleration of crystal formation and the growth of a mat of fine needle-like crystals. . .

Hard to keep a good smooth liquid interface going when things keep blowing up in there, that's for sure. Explosions are definitely underappreciated as a mixing technique, but in this case, they are keeping you from forming any larger crystals, a development which the paper says, with feeling, "should be avoided by all means". But it's time to reveal something about this paper: all this mercury azide stuff is just the preparation of the starting material for the real synthesis. What the paper is really focused on is the azide salt of Millon's base [Hg2N+].

Now that is a crazy compound. Millon's base is a rather obscure species, unless you're really into mercury chemistry or really into blowing things up (and there's a substantial overlap between those two groups). A lot of the literature on it is rather old (it was discovered in the early 1800s), and is complicated by the fact that it usually comes along as part of a mixture of umpteen mercury species. But it really is a dimercury-nitrogen beast, and what it's been lacking all these years - apparently - is an azide counterion.

There are two crystalline forms of that one, too, and both preparations have their little idiosyncracies. Both forms, needless to say, are hideously sensitive to friction, shock, and so on - there's no relief there. For the beta form, you take some of that mercuric diazide and concentrated aqueous ammonia, and heat them in an autoclave at 180C for three weeks. No, I didn't just have some sort of fit at the keyboard; that's what it says in the paper. I have to say, putting that stuff in an autoclave has roughly the same priority, for me, as putting it under my armpits, but that's why I don't do this kind of chemistry.

But the alpha form of the Millon's azide, now that one takes some patience. Read this procedure and see what it does for you:

Nitridodimercury bromide [Hg2N]Br (0.396g, 0.8mmol) is suspended in a saturated aqueous solution of sodium azide NaN3 (dest. ca. 3mL) at ambient temperature, resulting in an orange suspension which was stirred for ten minutes. The solution is stored at ambient temperature without stirring under exclusion of light. After one week, the colourless supernatant was removed by decantation or centrifugation and the orange residue was again suspended in a saturated aqueous solution of sodium azide NaN3. This procedure was repeated for 200 to 300 days, while the completion of the reaction was periodically monitored by PXRD, IR and Raman spectroscopy. . .

So you're looking at eight months of this, handling the damn stuff every Monday morning. The authors describe this procedure as "slightly less hazardous" than the other one, and I guess you have to take what you can get in this area. But the procedure goes on to say, rather unexpectedly, that "longer reaction times lead to partial decomposition", so don't go thinking that you're going to get a higher yield on the one-year anniversary or anything. What way to spend the seasons! What might occur to a person, after months of azidomercurial grunt work . . .surely some alternate career would have been better? Farm hand at the wild animal ranch, maybe? Get up when the chickens would be getting up, if they'd made it. . .head out to the barn and slop the wolverines. . .hmm, forsythia's starting to bloom, time to neuter the hyenas soon. . .

No, no such luck. The hyenas will have to remain unspayed, because it's time to add fresh azide to the horrible mercury prep. Only three more months to go! Sheesh.

Comments (42) + TrackBacks (0) | Category: Things I Won't Work With

August 27, 2013

Promise That Didn't Pan Out

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Posted by Derek

Luke Timmerman has a good piece on a drug (Bexxar) that looked useful, had a lot of time, effort, and money spent on it, but still never made any real headway. GSK has announced that they're ceasing production, and if there are headlines about that, I've missed them. Apparently there were only a few dozen people in the entire US who got the drug at all last year.

When you look at the whole story, there’s no single reason for failure. There were regulatory delays, manufacturing snafus, strong competition, reimbursement challenges, and issues around physician referral patterns.

If this story sounds familiar, it should—there are some striking similarities to what happened more recently with Dendreon’s sipuleucel-T (Provenge). If there’s a lesson here, it’s that cool science and hard medical evidence aren’t enough. When companies fail to understand the markets they are entering, the results can be quite ugly, especially as insurers tighten the screws on reimbursement. If more companies fail to pay proper attention to these issues, you can count on more promising drugs like Bexxar ending up on the industry scrap heap.

Comments (33) + TrackBacks (0) | Category: Business and Markets | Drug Development

Not Sent Out For Review

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Posted by Derek

Blogger Pete over at Fragment-Based Drug Discovery has a tale to tell about trying to get a paper published. He sent in a manuscript on alkane/water partition coefficients to the Journal of Chemical Information and Modeling, only to get back the "not sent out for review" response. That's the worst, the "We're not even going to consider this one" letter. And the odd thing is that, as he rightly put it, this does sound like a JCIM sort of paper, but the editor's response was that it was inappropriate for the journal, and that they had "limited interest" in QSAR/QSPR studies.

So off the paper went to the Journal of Computer-Aided Molecular Design. But as it was going to press, what should appear in JCIM but a paper on. . .alkane/water partition coefficients. There follows some speculation on how and why this happened, and if further details show up, I'll report on them.

But the whole "not sent out for review" category is worth thinking about. I'd guess that most papers that fall into that category truly deserve to be there - junk, junk that's written impossibly and impenetrably poorly, things that should have been sent to a completely different journal. These are the scientific equivalent of Theresa Nielsen Hayden's famous Slushkiller post, about the things that show up unsolicited at a publisher's office. If you're editing a science fiction magazine, you might be surprised to get lyric poetry submissions in another language, or biographical memoirs about growing up in Nebraska - but you'd only be surprised, apparently, if you'd never edited a science fiction magazine before (or any other kind).

But a journal editor can consign all sorts of papers to the outer darkness. At some titles, just getting a manuscript sent out to the referees is an accomplishment, because the usual response is "Stop wasting our time" (albeit not in those exact words, not usually). An author isn't going to be surprised in those cases, but getting that treatment at a less selective journal is more problematic.

Comments (17) + TrackBacks (0) | Category: The Scientific Literature

August 26, 2013

On Conspiratorial Thinking

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Posted by Derek

I recently had a e-mail exchange with someone who wanted me to read one of the many books out there that claims that some particular food additive is poisoning everyone. I'm not linking to the stuff, so I'll call the book's author Dr. Cassandra, for short. We argued about data and mechanisms a bit, but my correspondent also brought up what he felt were many other conspiracies around food and health, and I couldn't agree with him on any of those, either. That led to me writing this to him:

Let me get philosophical: one of the big problems with this sort of thinking is deciding what to trust. If you decide that Most Of What You Think You Know Is Wrong, then you have some work ahead of you. If these various authorities and well-documented sources of primary material are faked, then what *isnt'* faked? How do you know that the stuff you've decided to believe is on the level? My usual answer to someone who tries to convince me of the 9/11 stuff, etc., is to lower my voice and say "Well, yeah, but that's just what they want you to think". It's a universal answer. You can't falsify it.

Too often, what happens is that someone chooses to believe the things that fit their worldview, and dismisses the stuff that doesn't. That's human nature, but scientific inquiry is alien to human nature. If you start in with the conspiratorial stuff, then you end up skipping through the fields of data and sources, picking a daisy here and a cherry there, until you've made a wonderful centerpiece out of little bits from all over the place. And you can end up telling yourself, "See, this must be real. Look at this wonderful thing I've assembled, all the parts fit together so well - how can it be anything other than true?" But beautiful sculptures can be made from all kinds of found objects. If you start by assuming your conclusion - they're covering something up! - then you can get there any of a million ways.

So try this thought experiment: how do you know that (Dr. Cassandra) isn't just a plant? A false flag? Someone who's been put out there to make his beliefs look silly and under-researched (because believe me, he does)? Could someone in the pay of the Mighty Conspiracy do a better job of bringing its opposition into disrepute? That's the problem with conspiratorial thinking: the rabbit hole has no bottom to it. I refuse to dive in.

So my correspondent and I agreed to disagree. He thinks that eventually I'll see the truth of some of his beliefs, which I very much doubt. And I have little to no hope that he'll ever accept any of mine. The points made above have naturally been made by many others who've examined conspiratorial thinking, and I don't see much of a way around them. When you get to the Vast Overarching Conspiracy level of some of these schemes, you really do wonder how the believers manage to function. It's only a short step to the sorts of worldviews depicted in Diane Kossy's compendium Kooks: A Guide to the Outer Limits of Human Belief, which is worth a look if you've never encountered 100-proof paranoia before.

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Amgen Buys Onyx

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Posted by Derek

So Amgen's bid for Onyx look like it's going through, and the reaction of John Carroll at FiercePharma was to tweet "Expect big layoffs soon". He took some flak for being such a downer, but he's right, as far as I can see. Amgen isn't buying Onyx for their research staff, or any of their people at all. As that Bloomberg story linked to above has it, "Amgen to Buy Onyx for $10.4 Billion to Gain Cancer Drug".

That's Kyprolis (carfilzomib), their proteasome inhibitor, and that's all they need from Onyx, who bought the compound anyway when they acquired Proteolix a few years ago. So since I don't want to be a downer either, especially on Monday morning, I'd be interested to see if anyone can make another case. . .

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August 23, 2013

Options And Suchlike

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Posted by Derek

And after that mention of CEO pay, this sounds like a good time to link to this article from Nature Biotechnology. If you've ever been curious about why different companies pay out in stock options and/or restricted stock, this will satisfy your curiosity and more. A big part of the answer, you will not be surprised to hear, is the tax code, and if you're someone getting these kinds of compensation, you need to know some tax angles from your end, too.

And, of course, the type of award that works out best for the company doesn't always work out best for the grantee. Likewise, not every grantee will be best served by a single kind of award - it all depends on what you're trying to reward:

Although stock options continue to be a popular employee incentive device, in the past few years their advantages have been diminished through accounting and tax law changes, whereas their shortcomings have become more apparent in the biotech sector—in which a consistently growing stock price is far from assured, or even likely. As a consequence, biotech firms are moving away from an exclusive reliance on stock options and instead are using a mix of equity-based incentives, most commonly a combination of stock options and performance-based stock units.

From the perspective of a founder or other employee, the shift to a combination of stock options and some form of restricted stock or stock units should be welcome, making it less likely that the employee's awards will have no value at all. Unlike the corporate employer, an employee would prefer that restricted stock or stock units not be subject to performance conditions. . .

Definitely worth a look if you haven't thought about these details. After a good long stare, though, you may decide that the best course is to pay someone else to think about these things for you (!)

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What's a CEO Worth?

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Posted by Derek

In the case of Microsoft's Steve Ballmer, the stock market appears to be saying "About minus 18 billion dollars". As Alex Tabarrok notes here, that sort of puts average CEO compensation in perspective. . .do we have some bigwigs in this business who could do as much for their shareholders by following Ballmer's example?

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