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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 22, 2008

Open Source Science?

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Posted by Derek

The Boston Globe has a piece on the open-source science movement. Many readers here will have come across the idea before, but it’s interesting to see it make a large newspaper. (Admittedly, the Globe is more likely to cover this sort of thing than most metropolitan dailies, given the concentration of research jobs around here).

The idea, as in open-source software development, is that everything is out in a common area for everyone to see and work on. (Here's one of the biggest examples). Ideas can come from all over, and with progress coming more quickly as many different approaches get proposed, debated, and tried out. I like the idea, in theory. Of course, since I work in industry, it’s a nonstarter. I have absolutely no idea of how you’d reconcile that model with profitable intellectual property rights, and I haven’t seen any scheme yet that makes me want to abandon profit-making IP as the driver of commercial science. Of course, there's always the prize model, which is worth taking seriously. . .

Even for academic science, open source work runs right into the traditional ideas of priority and credit, and the article doesn’t resolve this dilemma. (As far as I can tell, the open-source science advocates haven’t completely resolved it, either). There’s always the lingering (or not-so-lingering) worry about someone scooping your results, and for academia there’s always that little question of grant applications. There have been enough accusations over the years in various fields of people lifting ideas during grant proposal reviews or journal refereeing to make you wonder how well a broader open-source system would work out, given the small but significant number of unscrupulous people out there.

On the other hand, maybe if things were more open in general, there would be less incentive to lift ideas, since the opportunities to do so wouldn’t be so rare. And if someone’s name is associated from the beginning with a given idea, on some open forum, it could make questions of priority easier to resolve. A subsidiary problem, though, is that there are people who are better at generating ideas than executing them – some of these folks, once unchained, could end up with their fingerprints on all sorts of things that they’ve never gotten around to enabling. Of course, that might be a feature rather than a bug: people who generate lots of ideas are, after all, worth having around. And over time, there might well be less of a stigma than there is now for someone else to follow up on these things.

The thing is, science has already been a form of open-source work for hundreds of years now. It’s just that the information has been shared at a later stage, though presentations and publications, rather than being put out there right after it’s been thought up or while it’s being generated. That’s why I always shiver a bit when I read about how long Isaac Newton waited before writing up any of his results – if Edmund Halley hadn’t pressed him to do it, he might never have gotten around to it at all, which would have been a terrible tragedy.

And it’s why stories like those told of physicist Lars Onsager strike me as somehow wrong. Onsager was famous for only publishing his absolute best work – which was pretty damned good – and putting the rest into his copious file cabinets (example here). (A related trait was that he was also apparently incapable of lecturing at any comprehensible level about his work). Supposedly, younger colleagues would come by once in a while and tell him about some interesting thing that they’d worked out, and ask him if he thought it was correct. Onsager would pause, dig through his files, pull out some old unpublished work that the new person had unknowing duplicated, and say “Yes, that’s correct”. It seems to me that you don’t want to do that, withholding potentially useful results for the sake of what is, in the end, a form of vanity.

And although I'm not exactly Lars Onsager, this is as good a time as any to mention that my summer student, who’s finishing up in the lab this week, has been able to generate a lot of interesting data, and that I’m going to be trying to write it up this fall for publication. Readers may be interested to know that this work is based on more ideas I’ve had in the vein of the “Vial Thirty-Three” project detailed here, so with any luck, people will eventually be able to see some of what I’ve been so excited about all this time. And that’s about as open-source as this industrial scientist can get!

Comments (9) + TrackBacks (0) | Category: Birth of an Idea | The Scientific Literature | Who Discovers and Why

October 23, 2007

Vial Thirty-Three, And More

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Posted by Derek

My apologies for no post today - home events kept me away from the computer for a while, but everything's settled back down now.

I've had several e-mails the last couple of months asking about "Vial Thirty-Three", the saga of which can be found (in reverse chronological order) here. (More specifically, the first time that particular experiment worked was the May 18, 2006 entry, and you can scroll up from there if you wish). When last heard from, I was cranking away on a batch of experiments to finish before the Wonder Drug Factory closed its doors at the end of January.

The last ones got run just before they pulled the electrical plugs out of the walls, and a lot of interesting things came out of them. They were interesting enough, in fact, that they suggested a whole new series of ideas to me during the months I was between jobs. Of course, that did little good, since this isn't the kind of stuff that you can easily pull off in your basement.

But I'm very glad to report that my current employer is interested in this sort of thing, and in plenty more weird stuff besides. That's the good news, and good news it surely is. I have an explicit mandate to look at ideas and technologies beyond what the company is currently doing, and a group to tackle these things full-time. This is just the sort of thing I like to do, and having it as my main job responsibility is so enjoyable that I may never get used to it.

The bad news is that I won't be able to talk about what I'm up to. At the Wonder Drug Factory, my odd experiments were a sideline and were a long shot to work at any rate. I felt safe talking obliquely about them. But now I spend my whole day on this kind of thing - the mutant progeny of Vial Thirty-Three and several other similarly odd ideas. It's a wonderful feeling to see this sort of thing get resourced and watch it move forward, but it's all completely proprietary.

But even if I can't say much, I just wanted to let people know that things are continuing. I'm doing full-time what I used to have to squeeze in as a sideline. Working on this kind of idea has been, in retrospect, one of the best decisions I ever made as a scientist. If any of you have some wild thoughts about experiments that sound a bit weird, but just might work - well, my advice is to somehow make time for them. Sometimes they work. . .

Comments (6) + TrackBacks (0) | Category: Birth of an Idea

January 24, 2007

Back on the Air

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Posted by Derek

I just wanted everyone to know that things have been quiet here because of some Movable Type maintenance behind the Corante scenes. Things seem to be working now, though, and rather more zippily than before. There seem to be a number of comments that were backed up in the pipes which have now appeared, too. I have a backlog of things to talk about (Pfizer! Dichloroacetate!) and regular blogging will resume this evening or tomorrow morning. Even though I'm soon to be unemployed, the blog will live on.

Another update: my manuscript for the "Vial Thirty-Three" paper has been put on hold for a bit, because of some data in it, not related to its main point but still unremovable, that need to wait before being disclosed. A little later on this year I should be clear to publish, though. It's frustrating, but since I did this work at the company's expense, they certainly have the right to say when it gets released.

Comments (4) + TrackBacks (0) | Category: Birth of an Idea | Blog Housekeeping

November 15, 2006

Vial Thirty-Three: Warp Drive

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Posted by Derek

As I mentioned the other day, I'm sprinting to finish some last experiments on my side project. These are all on the "vial thirty-three" system that I first described here and finally got to work reproducibly here. Looking back, I remember how surprised I was earlier in the year when I first saw this experiment work. Figuring it out has been like building an invisible ladder and then climbing up it, watching the rungs become solid under my feet.

Now, of course, I'm pulling out all the stops there are to pull. There are so many other experiments that I've been planning for and trying to do, but they won't get done, at least not here. I have to do everything I can with what I have on hand, because there's no time to make anything new. The publication that comes from this won't be as sweeping a story as I'd like for it to be, but it'll do.

But I'm accomplishing more in a few days than I have in months, because, sadly, there's no one competing for any of resources I need. Compounds from the repository? They're ready inside of an hour. More biological materials from the labs in the next building? They're giving me whatever I want, because all the projects that had first call have been stopped. The mass spectrometer downstairs, an essential piece of equipment for me and the largest single bottleneck I've faced? It's wide open as of tomorrow. I don't have to get in line any more; there is no line.

I went downstairs and loaded up one of the NMR machines with a day-long queue of proton and carbon spectra - in fact, they're still going and they'll be running all night. If I'd pulled that a month ago, someone probably would have gone out to the parking lot and slashed my tires. Now I'm the only person using the machine at all. No one cares. This brief, strange interval has been like having my own research institute, and I doubt if I'll ever see anything quite like it again. Everything's going perfectly, because everything's going away.

Comments (11) + TrackBacks (0) | Category: Birth of an Idea | Closing Time

November 13, 2006

The Race Is On

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Posted by Derek

Friday afternoon was quite strange. There had been another meeting to explain to people what the timetable would be to close down the site, but I left during its question-and-answer period. . .to go and set up an experiment. A half an hour later, colleagues of mine from down the hall were coming back from the main auditorium, talking among themselves about job searching and severance, and staring at me in disbelief as they walked past my lab bench.

You see, if I'm going to get a good publication out of my idea, I'm going to need some more data. For one thing, I need to go back and run some of the things I've already done, but this time at least in triplicate, so I can plot the data with error bars. Before I was running in duplicate, trying to save some of the harder-to-obtain reagents for later experiments, but that's not going to be an issue now. Inside of a couple of weeks, there aren't going to be any more experiments to run, because we're going to be shutting down the labs.

In addition to the repeats, I'm going back to my main sequence and setting up some new experiments which will help support my conclusions in a paper. Friday afternoon's run was a large one in that category, and (needless to say) it had better work. I'm not going to get much time to troubleshoot. I had been working on a different series of compounds, but there's not going to be time to finish that area, so it has to be thrown over the side.

So there I was, using some pipets that were left over when the company laid off a hallway full of biologists two years ago. I have no idea who the equipment I'm using belonged to, but I knew everyone over there. And the vials I set up went into a plastic rack, which is still labeled with the name of a lab associate who was let go about a year ago when another hallway was cleared out. I'm using reagents from projects that have been told to stop, trying to generate data before the analytical lab has to shut down. No wonder people were looking at me as if I'd lost my mind - if I had the time, I'd stop and stare, too.

Comments (13) + TrackBacks (0) | Category: Birth of an Idea | Closing Time

November 10, 2006

Publish, Then Perish

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Posted by Derek

It's not my intention to turn the site into a Saga of the Job Hunt, although that will be a recurring subject for a while. (I'd like to thank everyone for their expressions of support in yesterday's post, by the way. Much appreciated). The immediate future is fine - I'll still be at the workplace into December, and my lovely-parting-gifts package from the Wonder Drug Factory looks like it can take me a good way into next year if needed.

One interesting side effect of all this has to do with the side project described (elliptically) in the Birth of an Idea posts. Weirdly, the rapid end of normal research work at my site has opened a window of opportunity to get some of my off-the-radar samples looked at, and I plan to take advantage of that. I'm setting up a good-sized run of experiments to go over this weekend, for example.

I also hope to write up these results as quickly as possible, and for a better journal than I've appeared in to date. So here's a question: which journal? I think that this has a good shot at Angewandte Chemie or JACS, but I'm also considering really going for broke and sending it somewhere like Science or Nature. Can anyone speak to the reception that organic/medicinal chemistry manuscripts get in these venues? And are there other places I should consider (PNAS, for instance)? I realize that it's hard to judge this sort of thing without knowing quite what the manuscript is about. . .

Comments (9) + TrackBacks (0) | Category: Birth of an Idea

September 28, 2006

The Horse Latitudes

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Posted by Derek

I haven't given any updates on my side project recently because, well, there hasn't been much to update. Progress has stalled, for several reasons - instrument difficulties, power outages, people (including me) being out of town, resources being shifted around. This sort of work is particularly vulnerable to that sort of thing, because it exists through the sufferance of others. It's always been a "work on this after everything else is taken care of" project, and recently everything else has been having its innings.

I have a backlog of completed experiments in the freezer, waiting for a chance to get run, and I'm working on the design of several more. One thing that window-of-opportunity projects force you to do is make the most of the chances you get, so experimental design becomes more crucial than ever. I can't just run the first thing that comes into my head - odds are that it won't be the optimum use of the time and resources. I can usually think up something better if I spend more time thinking about it. Even so, I've had about all the time to think that I can handle for now, and I'm working on ways to get things going again.

Another odd feature of this work is the solo nature of it. I'm used to working in teams, which is how the drug industry operates the overwhelming amount of the time. That's because we have to have people who specialize in so many different areas, but there's an operational aspect to it that doesn't get mentioned much. In a team environment, people have to get things done because someone else is waiting on them. The biologists running the assays are waiting on the medicinal chemists for compounds, who are waiting on the assay numbers to see what to do next, and the same goes for formulations, metabolism, the in vivo assays, and all the rest of it.

But working alone is another story. No one is waiting on these results in the same way as in a normal drug discovery project. Many of my colleagues are interested in what's going on, but I'm the main customer for my own data, for now. If I completely stopped doing this project- walked away and never came back - some folks would eventually ask me about whatever happened to that wild idea of mine, but most wouldn't. And it wouldn't take long for the memory of the whole thing to get buried under the steady pile-up of new work.

No, no one's pressing me to do this but me. It's a different sensation from the industrial research I'm used to. For everything else I've worked on, I've known that if I left the project it would roll along without me, but not this time. This idea would die immediately if I took my shoulder off the wheel, but I'm not going to let that happen.

Comments (1) + TrackBacks (0) | Category: Birth of an Idea

July 27, 2006

Good News, Now That I Think About It!

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Posted by Derek

I have the results of my latest experiment. A thing of beauty it isn't - two of the four control arms showed false-positive effects in their blank runs, which makes interpreting them impossible. Those of you who've been following this story - and you have my sympathy - may recall that I saw this exact thing happen before. I wondered for a good part of the day why that might have happened, and maybe I've become slightly more intelligent in the intervening weeks, because on the drive home an idea hit me that would explain it quite well. I'll set up a short run of experiments to go over the weekend to test that out - if I'm right, it's an avoidable artifact and a complete red herring. Another arm of the experiment was a check on whether I could get away with running these things for a shorter time course, and the answer to that is: nope, I can't.

But there were good parts: the effect I'm looking for, the "Vial Thirty-Three" experiment, did repeat again, which is always reassuring. And the two other control arms behaved normally in their blank reactions - no weird positives - and they did just what I hoped they would do under the experimental conditions. This is good news, because they have very little in common with each other, and it's hard to see how they could do the exact same thing unless my hypothesis about them is correct. The more I look at those numbers, the happier I get. It's been slowly dawning on me that these may be the results I'm looking for.

But before I can be sure about that, the next item is to see if I can explain those blank-vial positives, and to also try a couple of variations on the runs that seemed to work. There are some minor changes I can make to them which should tune them up and down or flip them back the other way, and it's time to see if they're thinking the same way I am. I think I can feel the ground becoming more solid under my feet, though. . .

Comments (5) + TrackBacks (0) | Category: Birth of an Idea

July 25, 2006

Back To Life

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Posted by Derek

It's been a little while since I updated everyone on my long-running series of experiments, but I do have some news. At last report, I'd set up a large crucial experiment, and actually seemed to get it to work in the notorious Vial Thirty-Three. Of course, when you get something remarkable to happen in the lab, the first thing to do is see if you can make it happen again, and that's where the trouble started. The first repeat was rather nasty, and the second one was no better. I was baffled, since the first run had looked so promising.

My colleague Joanne, who was analyzing these samples for me, was puzzled, too, but she at least knew something to do about it. There's a huge benefit to working with people who know what they're doing. She took that third run and ran the samples for me again, this time in a much longer gradient on the LC/MS. (For the non-chemists out there, this means that the purification part of the method was extended, spreading out the various components of the mixture more). The control vials looked just like they had in the first run - not much, which is what controls are supposed to look like. The experimental vials had looked the same way, though, but with this new run my data appeared as if the results had come out from behind a cloud. Suddenly it looked like the first run again!

They'd been in there all along, as it turns out, and a cloud of ion suppression is what they were hidden by. This is a real problem with mass spec methods using mixtures of proteins (and the stuff that keeps them happy). There are a lot of reasons for this, only some of which are well understood, but having your analytes disappear and reappear unpredictably on you is apparently a widely shared experience.

I tried to see if there was some single component in my brew that I could leave out and thus fix my problem, but I should have saved my effort. That rarely seems to be successful - the real solution, as would have been clear to a real chemical biologist, is to run things the way you have to, and then clean up your samples before they go into the machine. The best way to do that is probably solid-phase extraction (SPE), which entails loaded your mixture onto some sort of powdered polymeric stuff which binds the analyte you care about. That lets you wash all the gunk out of the system, and then you use a different wash to elute the good stuff.

Here's an older review that illustrates the principle. These days, there are dozens of competing SPE technologies from all the major lab vendors. I evaluated a set of the more popular ones by setting up a row of dummy experiments - all my proteinaceous stuff, spiked with a constant amount of my desired product. All of them improved things, but one in particular (the Waters Oasis MCX, for those curious) seemed to do the best job, although I'm sure that there are others that would work as well. The method I worked out for it was the most complicated of all the ones I tried, but it's probably washing out the most sludge, too, because I'm getting ten- to twenty-fold more signal than I did before.

So, late last week I set up my first "Vial Thirty-Three" experiment again and worked it up with the SPE. It reproduced perfectly, to my great happiness, which takes me right back to the edge of things. Before I left the lab on Monday, I set up another run, this time with six different control and experimental arms, in duplicate, the most comprehensive look at this effect I've ever taken. I'm working it up today. Results in a couple of days, most likely. I'll keep everyone informed.

Comments (7) + TrackBacks (0) | Category: Birth of an Idea

June 11, 2006

Vial Thirty-Three: The Third Run

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Posted by Derek

Friday afternoon I got my results for the repeated experiment I spoke about here. Unfortunately, it matches the second run (the one that looks like garbage) rather than the first one (which looked like something wonderful). Unless I can think of some reason why that first run was different than the other two - and I was trying to make all three exactly the same - this forces me to conclude that the first experiment was some sort of false-positive artifact.

That's particularly hard to take because it looked so believable. The few colleagues I showed the initial data to were impressed by how clean it looked. And it made chemical sense as well, but that's all very close to being beside the point. I'm just glad that I didn't run up and down the halls showing it off, but I've been doing science too long to do that with n-of-one data, and this is a good illustration of the point.

So, what next? Well, when I set up that first experiment, I also ran another one on a different system, which has been in the freezer since then. It appears that freezing these experiments doesn't hurt them, so I'm going to try to thaw those out and get them analyzed. And none of this affects the positive results I spoke about here, on the model system. Those actually have repeated and made it past the control experiments. I've got an extension of that work coming up as well.

What I may have to do is fall back to the model work and beat on it some more. It looks like I need to see if I can understand more of what's happening before I try these gold-medal real world experiments again. I still have something - just not as much as I thought I did a couple of weeks ago.

Comments (3) + TrackBacks (0) | Category: Birth of an Idea

June 6, 2006

Vial Thirty-Three Rides Again

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Posted by Derek

Well, I got my repeat experiment set up before leaving work today. I could think of one variable I hadn't controlled for head-to-head yet, so I set up an extra couple of vials for that one. I'll try to get them analyzed tomorrow afternoon or Thursday morning, depending on how busy they are downstairs.

Getting this experiment going was a different feeling than when I ran it that Saturday. I was very eager and nervous that day, because I'd just had potentially great results and was ready to verify them as quickly as I could. (I had no way of knowing that the instrument needed for that was going to be out of service for two weeks, naturally). Today's repeat had some nervousness to it, but it was more along the lines of dread than the earlier anticipation.

I'm worried now that what I saw the first time is some kind of artifact, caused by something I haven't been able to anticipate. It looked very orderly, very clean, and quite believable, in its spectacular way. But yesterday's data had a more familiar look to it. It's really quite rare to get experimental results that are totally unequivocal - so many of them are a mixed, partly inexplicable bag. "Tell me - yes or no!" the experimentalist shouts, and the reply comes back "Dunno. . .sort of. . .I think. . .but maybe not, y'know?"

So by those standards, the first experiment, clean though it looked, is the suspicious anomaly. Here's hoping I'm wrong about being wrong.

Comments (4) + TrackBacks (0) | Category: Birth of an Idea

Vial Thirty-Three: One Up, One Down

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Posted by Derek

I finally have some more news about the experiments I spoke about here. The instrument used to analyze them broke down completely - not my fault, they tell me, but perhaps they're being kind - and came back on line just in the last couple of days. Yesterday we took the samples out of the freezer, where they'd been living for two long weeks, and ran them late Monday afternoon.

And the data make no sense to me at all. For example, some of the vials that were designed to shut down the effect I'm seeing actually made far and away more product than anything else. That's so odd that it doesn't even make sense as a negative result, which would have had those vials acting the same as the others. I can't come up with any reason why they'd be the best in the lot, that's for sure. There's also a lot of scatter between some of the duplicate runs, which leads me to hope think that this wasn't a failed experiment as much as a bungled one. Whether I hosed it up while working on it that Saturday, or whether it didn't take well to sitting in the freezer, I don't know.

Of course, it could be that these ugly figures are the real results, which would fit with Nature's well-earned reputation for heartlessness. There's only one way to find out - I'm setting everything up again today, with a few more variations to address any of the other variables I can think of. My first data still look so clean that I'd hate to think that this latest junk is the real face of things. But we'll know soon. I'll keep everyone informed.

Comments (0) + TrackBacks (0) | Category: Birth of an Idea

May 22, 2006

Mid-day Update

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Posted by Derek

I know I have some people stopping by to see how the experiments I described on Saturday have turned out. Well, the runs that I did late last week were not kind to the instrument they ran through, so one of my colleagues is now trying to get the machine back to its usual state. I'm ready to go as soon as things look normal, which could be this afternoon. If not, I'll put everything in the freezer and we'll run 'em tomorrow. And yes, the suspense is getting to me.

Comments (3) + TrackBacks (0) | Category: Birth of an Idea

May 20, 2006

Minute by Minute

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Posted by Derek

Well, it's about two in the afternoon here on Saturday. I don't blog from work, but this isn't exactly a workday, is it? I'm here to set up my control experiments that I spoke about, and let me tell you, it's quiet around here. There's not a lot of work done on weekends in industry - in fact, it's discourated, for insurance reasons. Just from the standpoint of common sense, it's not a good idea to come in alone and set up a big dialkylzinc reaction or a high-pressure hydrogenation when there's no one in sight.

But I'm not using anything nasty in these experiments - heck, I could probably drink some of the solutions, although that would be a pretty expensive cocktail, and three hundred microliters wouldn't be very refreshing. Right now I'm waiting for some stuff from the freezer to come up to room temperature. Then, as Portnoy's therapist said, we may perhaps to begin.

(Ten minutes later): The frozen stuff is about thawed out, and in the meantime I went down and borrowed a half-mL of reagent from the biologists downstairs. (There's no sign of life in their labs today, either). It's a common enough chemical, but it's not something you'd find as easily in a chemistry lab. (Keep in mind that biologists have things like reagent-grade olive oil in their cabinets). They had a one-liter bottle of what I needed sitting around, so I think my 500 microliters won't be a problem.

(Five minutes later): OK, things look ready to go. I've got some fresh solutions made up, labled by hand on the sides of the glass vials in the traditional blue Sharpie. Now to get things in the vials. I'm running ten vials today - five experiments, each in duplicate. There's a repeat of the vial thirty-three run that looked good last Thursday, of course, and a repeat of the corresponding blank control. Then I'm running three more controls, each of which should knock my unusual effect back down to nothing in a different way. If these go off the way I hope, it'll be pretty convincing evidence that I'm right.

Of course, as I've written before, these are nerve-wracking experiments to set up, because (looking at them another way), what I'm trying to do is try as hard as possible to kill off my exciting results. If I were dealing in mystic revealations here, once would be enough - heck, that first moment of inspiration several years ago would be enough. But for scientists and engineers, no one believes in anything until it's been done again, over and over, and until it's resisted strenuous attempts to make it go away. If's perverse, but it works. Now to the lab bench.

(Over an hour later): Man, that was unpleasant. Took a lot longer than I figured. For one thing, I messed up one calculation and had to redo a few vials. Another problem is that since there are five arms to the experiment, each with two vials, it means that I couldn't save much time by making stock solutions and portioning them out. Each vial was more of a hand-crafted affair. But they're all done, and sitting on my lab bench, where they'll stay until Monday morning. During the day I should be able to get them analyzed, and if all goes according to plan, I'll know Monday afternoon if I'm looking at something wonderful, or yet another handful of dry leaves and lint.

Comments (7) + TrackBacks (0) | Category: Birth of an Idea

May 18, 2006

Vial Number Thirty-Three

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Posted by Derek

This morning I got the results in from the first experiments that I spoke about here. Most of them did nothing at all. Nothing in the blank controls, nothing in the experimental wells.

There were forty vials to examine, and there was nothing to report for quite a while. But vial number 33, that one appears to have worked. If the reading from it is accurate. I can hardly believe what I'm seeing,

But einmal ist keinmal, especially where wonderful results are concerned. I'm coming in over the weekend to set more controls and repeats to have them done on Monday, which is the next chance I'll have to get anything analyzed. If I can make it happen again, I've just had the most interesting and important result of my entire scientific career.

And I just can't tell you how surprised I am at that possibility.

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May 14, 2006

Cliff Diving

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Posted by Derek

I haven't given any updates on my side project experiments recently. I've been preparing a number of starting materials and getting things ready for another big run. I'm using a number of systems that people use for other (more normal) purposes at work, but I'm bending things around so much that everything has to be re-checked. And I don't have priority over anyone, which is as it should be for something this speculative, so I have to work in between what everyone is supposed to be doing. Finally, I think everything is in order. I'm setting up a new round of experiments tomorrow.

It'll be a few days before I know if anything has worked, though. The experiment itself is rather lengthy, and the analysis isn't trivial, either. I actually have two or three different variations of the idea all about ready to run, so it's going to be a real flurry of activity by the long, slow standards I've been working by. I wanted to take more risks in my research this year, and here they are, reporting for duty.

Are any of these things really going to work? I wish I could evaluate the chances better, because that would help me figure out what to run next. As it is, this is such terra incognita stuff that I just don't know what to expect. I shouldn't complain about that, though, since that's what being a scientist is supposed to be about. It's an odd feeling to be living it, though. There's nothing quite like it.

I've been out on several edges of knowledge over the years. Plenty of chemists experience the no-one's-ever-made-this-molecule edge (in industry, of course, we count on that being the case). You can get out to that territory pretty quickly, even now. Then there's the discovery of a new reaction, the no-one's-ever-made-something-this-way edge of knowledge. I've been in on one or two of those, too, and there are research groups that make it their whole business.

But this one is really out there, to the point where colleagues raise their eyebrows at me when I explain it to them. This, though, is where I've wanted to be ever since I started doing research. Win or lose, I feel privileged just to set experiments like these up. Here we go.

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January 2, 2006

A Scientist's Resolutions

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Posted by Derek

1. Get more done in the lab. That's a pretty generic one, but it gets harder to do the further on you go in your career. At the point I've reached, I could spend a good amount of my time hiding out in my office, banging away on the computer, and no one would be the wiser. No one including me, unfortunately, which is why I need to resist doing that when there's something more useful available.

2. Clean up my hood. I have piles of junk in there now, and while I can work around it, there's no reason to. I'd be more comfortable - and who knows, maybe even more productive - with some of it cleared out. The lab bench needs some pruning, too, since there's stuff there from three projects ago with months of dust on it. Out it goes.

3. Get more done in the office. What with number 1, that doesn't leave me much room to maneuver, does it? What I mean is to do the office work I need to do, without using the lab as a place to hang out and procrastinate. Perhaps these two resolutions could be combined into a broader one, a researcher's version of Kant's Categorical Imperative: to use both sides of my job as ends in themselves, not as means to avoid each other.

4. Go out on more limbs. This is another thing that I can afford to do at this point, and I should do it more often. I have some opportunities to try low-percentage high-reward ideas. Not everyone does - if I've got a special function, that's probably it. ("Bothering people" doesn't count, I'm pretty sure).

I can think of an example that touches on all of these simultaneously. Long-time readers will recall my occasional series on a research project I've been working on for the last two or three years. It's the very definition of a high-risk high-reward idea, and one of my better moments in 2005 was finally getting it to work a little bit. It's been somewhat stalled the last two or three months, though, partly by factors out of my control.

But partly not. I haven't been pushing the stuff as hard as I should have been, either. And I don't hesitate to diagnose fear as the cause. You've probably heard that line about how to travel hopefully is better than to arrive - well, it's not true if you've chosen your destination wisely. But it does show how it's easier to stay in the almost-done state rather than reach a resolution. After all, what if I'm wrong? What if the effect I've seen can't be generalized to anything useful, and I've worked myself up over a triviality? Isn't it better to stay where I am, where I can still think that I'm on to something?

Well, no, it isn't. But I need to keep reminding myself of that, and not look for excuses when it comes time for another key experiment. And that's my advice to the part of my readership that does research for a living: take some risks in 2006. I'm going to. Let's discover something for a change.

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September 25, 2005

Report From What I Think is the Frontier

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It's been a while since I spoke about the run of experiments that I've been doing. Things are going very well, although not quickly. The combination that seemed to work for me back in June (see the 6/23 post here) has repeated cleanly several times now, with new control experiments and fresh solutions of everything. And since then, I've found a couple of others that also seem to give the effect I'm after and they hold up, too. I'm having to make the mental adjustment of realizing that this stuff is real and reproducible.

I mentioned that I was going to present my results inside my company. That went fine, I think, with about the same number of people leaving the room thinking that I was nuts as came in. Mind you, there was some turnover in the rosters of people holding each opinion. But I've been given a bit of room to work on what's now generally known as Derek's Crazy Idea. I have a two-week experiment going on to get some kinetic data on things - how quickly does this stuff come on, how high can it go, when does it start to level off, and so on. And I'm getting geared up for an extension to a completely different system, one that's much less of a test bed and much more of a real-world application.

That makes me rather nervous, because there's plenty of twangy tightrope stretched between those two platforms. My preparations include gearing up for a huge range of reaction conditions, because what my work thus far has shown is that I don't have a clue - yet, anyway - about what's going to work and what isn't. When I think about how close I came in the first system to never seeing anything at all, it makes me want to sit down for a while. How many other interesting things have I missed in my research career, slipping past me by only a couple of millimeters and still leaving no trace?

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August 16, 2005

Experimental News

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I set up another run of experiments in my long-running series today. I'm repeating the best results from last time (the previous post in this category), with fresh samples of everything (just to be sure that there wasn't something odd about the last batch, which seemed to work so well.) There's a new type of control in there, too, off in another direction from the ones I've run before. And I've made several new compounds to test, all closely related to the things that seem to have worked.

That's been a big part of the delay. I've exhausted most of the commercially available starting materials by now - as I narrow down to the most promising structures, I find that I have to make a lot of my starting materials myself. Some of them are easy to whip out, but I still have to purify them, and all these things take time. And, of course, none of this is officially what I'm supposed to be doing, so I have to work these things in as I can.

I've also accepted an offer to present the whole idea in a public forum for the first time. Well, an inside-the-company public forum, that is. I've grabbed folks by their shirt collars and scribbled all over their office whiteboards during the last couple of years, but this will be the first time I've put everything together into a real presentation. My submarine project is beginning to surface.

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June 23, 2005

News Flash: I May Not Be a Fool

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Posted by Derek

I now have my experimental results, at long last. And, well, I have to say that I seem to have something.

This batch was set up with fifteen different chemical structures, and I was looking for the same effect in each run. For each structure, there was an experiment that should have shown the effect I'm after, producing a new product, then a control (without a key ingredient) which should have shown little or nothing, and another control (with the key ingredient present, but with another compound added that should have blocked it from doing anything.)

I thought at first that I had fallen completely on my face, because as I looked over the first five or ten structures, I saw the same discouraging pattern. Next to nothing in the blank control runs, which was fine. But the numbers from the corresponding key-ingredient experiments were identically low, which was the inescapable sign of nothing going on. I'd also seen some where the experimental run showed something, but the corresponding blank showed the same exact levels - again showing that my experimental conditions weren't changing anything, but that I just had a high background rate of reaction.

I was using strong language by the time I got to number twelve, which showed a pretty high value in the experimental run. I looked over to the blank run, expecting to see the same levels, another high-background dud - but it really was a blank this time. Almost nothing there. The experimental run was at least fifty times higher. I held my breath as I looked at the second "inactivating control" run, and there it was -it went right back to the blank value, as it should if my hypothesis was correct. I had set up all the experiments in duplicate, and this morning I got the repeat data, which matched the first set very tightly. It appears to be real.

And to go along with this, these experiments also included the best candidate from my first attempts, the one that got me excited about running these follow-ups in the first place. It had made a lot of product again, although just three or four times the high background rate in the blank reaction, as it had been before. But had the inactivating control experiment knocked it back down to those values anyway? It had.

And both that one and the new winner are structurally quite similar, and they're the only two of that exact class that I've run. It's becoming increasingly clear to me that I finally have something that works, after three years of on-and-off attempts. I hardly know what to do with myself.

Well, that's not quite true. I have another variation ready to go, with ten or fifteen new structures of a different type, and I have time to incorporate what I've learned from this run before they go off. It's time to see just how far this stuff can be pushed.

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June 21, 2005

Data, At Last

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A rare mid-day update: finally, after weeks of delays, I'm getting the analytical data run on my most recent set of experiments. These are based on what looked like successful results back in April (see these posts for the details), and if I have any idea of what's going on, they should work.

And that's the scary part. Late this afternoon or tomorrow morning, I'll either know that I'm on the track of something interesting, or I'll have slid most of the way back down the hill. Again. It's been like this every time I've come up to a crucial experiment in this work. As I've said, scientific progress depends, to an unappreciated extent, on the willingness to look like a fool. It's tough work, waiting to find out if you are one or not. . .

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June 7, 2005

Experimental Update

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Since I mentioned a while back that I was setting up a crucial run of experiments, I thought I should let the (three or four) people who are following this story know what's going on.

What's going on is that I'm slowly chewing a hole through my desk. The instrument that I need to get these samples analyzed went down just as I was finishing up the experimental run. And that's not "down" as in "let's replace the fitting with a new one from the drawer here," that's "down" as in crucial-hardware-back-ordered-from-another-continent. As in two service techs up to their elbows in the thing for three days - that kind of down. As of today, the machine still isn't its old self.

My original run of experiments is probably untrustworthy at this point - I'm saving it to try out backup analysis techniques. I set up another run of fresh ones, which are now in the freezer, waiting to be analyzed when there's something to analyze them with. I console myself with the thought that they must have some pretty good stuff in them, because the universe is sure doing a good job of keeping me from ever finding out.

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April 27, 2005

Experimental Update, For Those Who Care

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Posted by Derek

Well, I got the results of my experiments this afternoon. There might be something there, but I'll have to see the rest of the data in the morning to be a bit more sure. In research, we live for slam-dunk experiments that really prove things, but most of the time we get this could-be might-be stuff.

Most of the reactions did nothing, which was disappointing. Two of them showed what could be a real effect, though, and those two were from the same chemical class. That could be telling me something, or it could be just a coincidence. The analysis of some duplicate runs of the same things will be ready in the morning, and I'll see.

If they repeat, that's probably good news. I'll then simultaneously narrow down and fan out in other directions. That is, I'll set those same reactions up again, and add a few runs that are controlled for against some other variables. On the other hand, if they don't repeat, then I first need to make sure that my wonderful pipetting technique isn't one of the causes, but then I have some other things to try on different systems.

One of the few things I can prove is that not every system I can set up has an equal chance of working - in fact, some of them definitely won't work at all, for reasons that can't be foreseen. Perhaps I've landed on one of these and need to get out into another area - or perhaps I'm just wrong from the start. It's too early, fortunately, to be able to prove that.

UPDATE: Well, all the experiments repeated quite nicely, which is something to be glad of. If I'm wrong, I'm wrong the same way every time. I'm already planning another run of stuff for sometime next week, and I won't inflict the details on everyone until they're finished.

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April 25, 2005

Live The Stereotype!

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Posted by Derek

Now I know why all the biologists I know are half-sane at best: it's all that pipetting. I set up my experiment today, in a 96-well plate (here's one similar to what I was using, if you don't know the beasts), and spent a good chunk of the afternoon pipetting in a few microliters of this and a few microliters of that. Over and over. A multichannel gizmo (like this one) would have helped, but only in the beginning. Everything else was special-ordered for each well, so this was going to take some time, no matter what.

Still, I'm glad to have finally fulfilled my research destiny. The biologist-holding-a-pipet shot is third in the pantheon of Cheap Scientific Shorthand images. Just ahead of it is Peering Insightfully Into the Microscope, and at number one (as I've written about before) is Looking at a Raised Erlenmeyer With A Thoughtful Expression.

The experiment will run until Wednesday morning. Then it goes to my colleagues downstairs for analysis, and it's possible that I'll start getting results on Wednesday afternoon. Otherwise, I'll just sit around on Thursday and stare at the phone until it rings. That always works.

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April 24, 2005

The Consolations of Pure Research

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Posted by Derek

I mentioned the other day that I'm getting close to another run of experiments on the research idea I've been messing with for a couple of years now. For those who haven't been following this tedious tale, so far I've had - well, I've had no real success at all. I thought at one point that something might have worked, but it didn't repeat in any detail.

So, why am I coming back for more punishment? Several reasons: for one thing, I can now think of possible confounding variables in the earlier runs that could have rendered them unable to work. (Many of these are addressed in the current experiments.) Second, I still - in the face of a fair amount of evidence, I admit - believe that this whole thing should work. Some roughly similar chemistry has worked for others, and I think that my modifications (which should make the final technique much more broadly useful, I think) aren't big enough to mess up the whole system.

And the third reason is that I enjoy this kind of work very much. It's a luxury to be able to work on your own ideas in industry, outside the bounds of a particular project, that is. (When we're working on inhibitors of XYZ kinase, I'm free, naturally, to have any ideas I want to about inhibitors of XYZ kinase.) Doing this kind of blue-sky side work is a nice change.

I'll know in the next couple of days if my colleagues in the analytical group are ready for me, and the first run of experiments will take a couple of days themselves. Then there's the time it takes to analyze them (on the instruments, that is - once I see the data, I'll know in a couple of minutes if things have worked out or not.)

Every time I come back to this work, I have a clearer idea of what's going on, and a better way to see it. If you keep doing that, you eventually break through. Right?

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April 3, 2005

Don't Talk To Yourself So Much

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Posted by Derek

I've been re-reading Francis Crick's memoir What Mad Pursuit, and this passage struck me:

". . .it is important not to believe too strongly in one's own arguments. This particularly applies to negative arguments, arguments that suggest that a particular approach should certainly not be tried since it is bound to fail. . .While one should certainly try to think which lines are worth pursuing and which are not, it is wise to be very cautious about one's own arguments, especially when the subject is an important one, since then the cost of missing a useful approach is high. . .

Be sensible but don't be too impressed by negative arguments. If at all possible, try it and see what turns up. Theorists almost always dislike this sort of approach."

Right on target. In my field, there is hardly an experiment worth doing that can't be objected to right at the start. Counterexamples abound, theoretical reasons why things won't work out are everywhere. Too sterically hindered, not nucleophilic enough, an interfering functional group somewhere else in the molecule, wrong solvent, wrong catalyst, wrong temperature, wrong everything. If you listen to every one of these objections, even when they're coming from inside your head, you'll never do anything at all. True, you'll never be wrong, but only at the cost of never being right.

This is on my mind tonight, because I'm getting close to a revival of a series of experiments that I've been messing around with for nearly three years now. It's a very interesting idea whose details, painfully, I'm not at liberty to lay out. Not yet. I'm reposting my writings on this work over in the Birth of an Idea category at the right, in case you're interested in seeing what scientific excitement does to a person.

The whole time, I've hardly had the tiniest bit of experimental success, it pains me to say. But I'm back with another variation. Every time I'm more sure that things are going to work. Perhaps, after two years of being quite wrong, I might make the switch to quite right. . .

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March 14, 2004

Mismatched Socks

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Posted by Derek

Some miscellaneous updates tonight, in addition to the note appended to the post below. It seems that Sunday nights don't often leave with time for more extensive blogging, and the world events of the last few days have made their claim on my attention as well. This isn't going to be one of those dull years, not that I expected it to be. In fact, I'm not sure when we're going to have one of those again.

Some readers (rather few) may be wondering what's been up with my long-running series of odd experiments, last seen crashing to earth in a rain of feathers and melting wax. I haven't set anything up in the lab since that, but I've been busy working on a presentation to go public (inside my company, anyway) with my ideas. The project, if it's going to work at all, is too big for me to do in the scientific equivalent of my garage. I'm going to make my case for some formal support, and it'll be interesting to see how that's received.


On another front, I wanted to mention that I closed out my short position in Imclone at about $45/share, a nice round loss from the $40 where I went short. I'm keeping an eye on the stock, and if it continues to rise (up into, say, the 60s with no change in the underlying situation), then I'll consider shorting it again. For now, though, discretion was the better part of a capital-gains loss. I continue to think that many IMCL investors suffer from an excess of optimism, but that's one of the engines of the market, isn't it? (I did make up that loss and more by shorting MSO, Martha Stewart's company, though. Write and I'll bore you with the details.)

And the Sanofi/Aventis dance continues, with Novartis hovering over the whole proceedings. This is yet another situation where those who say, don't know - because those who know aren't saying. Most of the public statements are designed to be, well, merely public statements, so their information value is questionable. It's going to be a while before we know how this one comes out, so I haven't been (and won't be) covering every twist and turn. If anything dramatic happens, I'll weigh in.

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January 25, 2004

A Little Ambiguity Would Be Welcome Right About Now

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Posted by Derek

My experimental results came in late Friday afternoon, and. . .well, rarely have I seen less encouraging data. It wasn't enjoyable. I was there as the numbers for each part of the experiment came through, and I could tell early on that I was in trouble.


So, here's the rundown: the repeat of my previous (putatively successful) experiment failed. Then the attempts to increase the effect failed at each point - if anything, things went down instead of up. Then the attempt to reverse the effect (in four different ways) failed, no doubt because by this time there really wasn't anything to reverse. The best-looking run of the whole afternoon was from this group - but it was, perversely enough, the one that should have been the most shut down. Ungood.


What now? The only way this experiment can be any kind of good news is if some systematic error disabled the whole thing. I would love to find out that one of the components was taken from the wrong vial, or was left on top of a hot plate or something. But that's highly unlikely. But what about that previous experiment, the one that led to this death-or-glory attempt? I'm going to be going back over that one, giving it a fishy glance in light of what happened on Friday. At this point, the hypothesis that best fits the data is that the encouraging results are wrong.


I may still be able to do one more attempt. There are a couple of oddities about this latest data set that I don't understand, and the idea is worth one more shot under the cleanest conditions I can think of. But that, for now, will have to be it. I'm going to have to go back to the drawing board and think about what's going wrong, see if there's some different way to realize what I still think of as a beautiful idea. There may yet be. Plenty of beautiful ideas don't work, though: beauty is necessary, but not sufficient.


Science is fun, it really is. And it's certainly damned useful. But it isn't easy.

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January 22, 2004

Dr. Lowe? I Have Your Hypothesis on Line Two

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Posted by Derek

I spoke a couple of weeks ago about my latest series of experiments at work, and I've had several inquiries about how things are going. Well, the whole shebang has been in the freezer, actually. The instrument that we need to analyze things (and the person who runs the instrument!) have both been occupied with an unexpectedly lengthy problem in one of our drug discovery programs. My high-risk side project takes a back seat to that, understandably.


But the thaw is coming. I was told yesterday that my samples have moved back to the top of the list, so it's possible that I'll start to get results tomorrow (and if not then, on Monday.) So, here we go. I think that these runs are going to be definitive, one way or another. There's always the possibility of a "maybe" answer when you do an experiment, but the key to successful design is setting things up so you don't get many of those. I think these results won't have too much ambiguity in them - they shouldn't. If they do come back fuzzy, it means that my mental picture of what's going on is faulty, even if my broad idea turns out to be right.


My whole idea is on the chopping block, and the knife is poised to fall. I'm going to be able to look back on this evening, this whole period, as either the last time when I still had doubts about this discovery - or as the last time when I still had hopes that it was real. Oh, science is fun - it really is. And it's certainly damned useful. But it isn't easy.

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January 12, 2004

If This Doesn't Work, There's Only Reality To Fall Back On

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Posted by Derek

Time for an update on my research, where I'm still working on the odd idea that I've been speaking about. In my last installment, I had what seemed to be good results from an experiment, and I was getting ready to set up some more control runs to see if things would behave as they should.


Well, those reactions are going right now, thanks to the efforts of a colleague in Biology. These experiments will be running all night (Monday EST) and finish off around lunchtime tomorrow. Then I'll take the solutions down to another colleague in our analytical department, and in the next few days, she'll tell me what's happened. The wait will not be an easy one. I can tell that already.


That's because this batch of experiments is actually a pretty strenuous interrogation. I've tried to set it up so that good results can come out of it only if there's something real going on. I think there is, of course, but it's impossible to say for sure. My results from the first experiments could be characterized as "consistent with my hypothesis," but that's all. Mind you, that's a lot better than the alternative, hoo boy, but there could be other (less interesting!) things they're consistent with.


But the reactions taking place tonight should sort things out, but good. This run has four different parts to it: There's a repeat of the most promising conditions from the first experiment, just to ask the most basic question (reproducibility.) A distressing number of interesting experimental results never poke their heads up again, so that's one hurdle. In the second part, there's a set of conditions that should cause a larger effect than I saw the first time. This attempt is being racheted up in two seperate steps. If it goes up nicely each time, I'll be very happy. If the results come back one-up, one-down, I'll be staring out the window a lot, trying to figure that out. And if they show no effect, well. . .


The third part reverses field: it's an attempt to completely abolish the effect, by a mechanism that should be quite specific to my hypothesis. This one's in two steps, too, in another attempt to see a dose-response relationship. Having this one come through, which would revert the system to the same results coming from the corresponding blank experiment, would be strong evidence that I'm on the right track. The reverse holds true, too, unfortunately - if there's no effect here, my hypothesis has taken a torpedo right in its engine room. (That blank experiment is running tonight, too; it's an important control for all these tests.)


And the last ring of this circus is another attempt to make my desired effect disappear. I've changed a chemical structure in a way that should make very little difference to anything, except in the case of my hoped-for mechanism. It should shut that down pretty cleanly. It'll be hard to hold on to my current idea if this doesn't work as planned, either. I'll have to fall back on experimental error, which is not the first explanation you want to reach for, or some other variable that has completely escaped my notice. Neither of those is a good bet at this point; it'd be a lot simpler to assume that nothing interesting is happening at all.


For readers outside the research arena, those try-to-kill-it experiments are a powerful and commonly used technique. It's hard to run them sometimes, because it's hard to escape the mental picture of your new phenomenon, just arrived into the world of physical experience, being scared back into its hole by the sudden advent of search lights and sirens. But, you know, there are a lot of things to work on in this world. And if you don't figure out what's real and what isn't, you can spend most of your scientific career doing the equivalent of digging holes and filling them back in. It's hard on a hypothesis, being put to the test like this, and I'm here to tell you that it's not all that easy on the person behind the idea, either. If something's real, though, it'll show itself - it'll have to show itself - no matter what nasty questions you ask. Better to ask them up front.

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December 7, 2003

Good News, Backing Slowly Through the Door?

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Posted by Derek

It's a good time to give a brief update about the experiments that I'm running at work. (The last time I spoke about them was here.) For those who haven't seen one of these posts, I've been chasing an odd idea for months now, on and off. So far, the tests that I've put it to have come up negative - or at least not positive, which is often something different. I've continued to refine my thinking about what's going on while searching for a better system to work with.

The other thing that newcomers to this site need to know is that I can't tell you exactly what this idea is. Now there'ssome great blog material, eh? But I'm hoping that folks will understand. If I were in academia, I wouldn't talk because I would be afraid that someone would scoop me and get priority by publishing first. Since I'm in industry, I worry both about that and the proprietary advantages that this stuff might bring. (If it works out well, there certainly could be some.) Actually, come to think of it, academics think that way too these days, don't they?

I'll try not to be too reminiscent of the South Sea Bubble scam artist that Charles MacKay talks about - the one who advertised partnerships for sale in "An undertaking of great advantage and no man to know what it is." He took in a large sum within a couple of days, and as MacKay tells it, he "was philosopher enough to be content" with his profits, bailed out to France and was never heard from again. At least I'm not selling shares.

On to the news. In my last, er, thrilling installment, I was about to set up (with the help of a colleage over in a pharmacology lab) a new experiment which would be the best shot yet. Well, it took a while to get this one analyzed, during which time the solutions sat patiently in the freezer. I had to remake a standard compound for my colleagues in the analytical group, and they had to work out good methods to run the samples with, which needed something else first, and so on. But we got things together last week, and got the data. And, well. . .the thing might have actually worked.

I was running four separate variations on the same system, and all four did some of what I wanted, apparently. They did it to different degrees, and in a pattern that (if it's real) is quite suggestive. But the whole thing was getting close to the limits of detection - not so close as to make the results totally suspect, fortunately, but everyone involved would be more comfortable with a higher signal/noise ratio.

These results have immediately suggested some follow-up experiments, which I'm going to do with the most promising of those four variations. There are three more components of the system that I'd like to vary. One of them should (helpfully) lead to a stonger signal, which should vary as a function of the component we're adding. That'll be a useful check. And the other two experiments will go the other way and wipe out the effect completely, each by a different route, but only if things are happening by the mechanism I'm postulating. These experiments will carve great swaths through Explanation Space, blanking out whole regions of potential false-positives.

And if these runs go according to predictions, well, I'm going to be in the position of the dog who finally caught a car. Scientists can relate to those dogs, you know. What makes us different from the dogs is, we all know just how we would drive the thing if we caught it, and just where we'd want to go. Woof.

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November 28, 2003

Waiting for the Metaphorical Phone to Ring

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Posted by Derek

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.

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August 3, 2003

Per Fits and Starts, Ad Astra

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Posted by Derek

Last summer I was working on an interesting chemistry idea. I posted about it on and off, in what was likely an irritating fashion - irritating because I could never quite go into just what the idea was. There were two reasons behind that: for one, my employer gets the rights to chemistry ideas that I work on in my employer's labs, and quite right. (The contracts that you sign when you join any research-based industrial organization are very, very clear on that point.) The second consideration is scientific priority, and scientific pride.

Now, what I'm doing isn't going to win me a Nobel prize, but it is a very nice idea, and one of the better ones I've ever had. So it would be more pleasing to me if I could get it to work with my own hands before letting everyone else take a crack at it. One problem is that I tend to work on things like this in jerky bursts of activity, and those don't come nearly as often as they should. Someone with more discipline would have made more progress, no doubt. A scientist who combined periods of free-association idea generation with stretches of well-structured lab work to follow them up would be the person to have around. I haven't met too many of those people, but they certainly exist. I'm not one of them.

I comfort myself by thinking that the folks with the most disciplined work schedules tend not to have ideas as off-the-rails as this one. It's a common complaint in the drug industry that the work is so ceaseless as to leave people with no time to think. And as I've written before, if you don't have some staring-out-the-window time, you don't have that many ideas. I know that when I've run a project myself, I don't as many good ones. There's no mental overhead left for them; I'm too busy making sure that everything's going the way it should. It's exciting, being at the head of a drug project, but it does wear you out.

Even when you're not running a project, there's always enough work to keep you busy. Keeping busy isn't the problem. The problem is remembering that "busy" doesn't always mean "productive," although they can be mistaken for each other in dim light.

I bring all this up because, as I mentioned a few weeks ago, I'm taking another crack at this stuff. I've been messing around with the idea(s) on and off over the intervening months, but a very good opportunity now presents itself. It's the same core concept that I've worked on before, but (for once) it matches up very well with the project that my lab is officially working on. If I can continue to keep on the tasks at hand, this coming week will see most of the groundwork laid, and the week after that should see the first runs of the real thing.

Here's hoping that I ignore all distractions, and have the nerve to put my favorite ideas on trial. That's the real problem with working on ideas of your own, ideas that you think have the potential to be really good. They don't all work. Most of them don't work. It can be more psychologically comforting to keep them in the "untried but promising" category, rather than find out if they're real.

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August 16, 2002

Here It Goes

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Posted by Derek

The research idea I've been alluding to recently gets a key test today. I've got two values for one of the variables (high and low, essentially) and four values for another. And I've thought up two control experiments for each of those eight cases, which narrows things down quite a bit: under this experimental protocol, good news would have a very good chance of actually being good news.

But bad news would have a pretty good chance of actually being bad news, too. I can think of more ways to see a false-negative than a false-positive, but I'm not sure how likely some of those really are. If nothing happens today, I've got some plans for a second run which would address some of those.

Of course, I'd rather not find myself in the familiar research position of looking out the window, wondering what went wrong. I'll know by later this afternoon. A colleague from another department is setting things up and will collect the data, and I won't be very far from my phone during that time, I can tell you. Waiting for this stuff is nerve-wracking - it feels like I've asked the physical world out on a date and I'm waiting to hear if it'll accept.

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Nature Stood Me Up

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Posted by Derek

. . .not for the first time either, and doubtless not for the last. For anyone stopping by to get an update on my experiment, well, not very much happened. The controls all worked about like I figured they would, but the real experimental cases refused to do anything. And the one run that perhaps moved off the starting point was the one that I least expected to see anything from.

My colleague is going to set up another run in a few days, this one under more forcing conditions (in case I've underestimated the ease that things should occur.) I can come up with a couple of other hypotheses to check as well (as I alluded to this morning.)

But what this means is that (even if my whole concept is right) it isn't going to be easy. It's not like the door is just swinging open to this new field I'm picturing. I'd wondered if it was just because no one had thought to give it a push. I still think the basic idea is sound (although I still have scant evidence for that belief,) but it's an open question how far it can be generalized. If it were as general as I'd hoped, this experiment probably would have worked, frankly.

So, if the door isn't just opening up, the next thing to do is pick the damn lock. I've been uncharacteristically quiet since I got the data today, while I absorbed it and thought about what to do next. But I feel things getting back to normal already. I've got another system to try next week (and I'm working on another new one after that.) And I've had a decent idea to address today's failure, just while sitting here tonight. I'll be back on Monday morning, trying something new. Fortes fortuna juvat.

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August 4, 2002

Close to the Vest

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Posted by Derek

Another line in one of the aforementioned Paul Orwin posts rang true for me. He was discussing some new ideas in antibacterial research, then brought himself up short as he got close to his own work: "In the highly competitive world of academic science, even a weblog is no place to divulge current research tidbits"

The same thing goes, with pistachio nuts and a cherry on top, for industrial research. I've hardly said a word about the actual work I do during the day, and I don't plan to, either. It's a pity, since it's been an interesting project with a lot of twists and turns, and it would have been a good illustration of what med-chem research is like day-by-day. But I'd have been fired long ago if I tried to do that, and rightly so. Like all other pharma companies, no one hears a word about what we're up to until we're darn good and ready to tell 'em.

That's what makes information such a strange commodity in the business. The Journal of Medicinal Chemistry("Jay-Med-Chem" to its friends) can be an interesting read, but only in a historical sense. Projects you read about there are either well along in the clinic, or well buried out back with grass growing over them. The same goes for presentations at conferences. When I see a poster from a drug company with a good crowd around it at a meeting, I always think of someone attracting birds by throwing stale bread on the ground.

I've been guilty of crowding around 'em, too, though. I've come back from meetings bursting with the latest news from other companies, as given in their presentations. But we all have to remind ourselves that these breaking headlines are like light from distant stars. Who knows what's happening there now?

This all applies to the research project that I've alluded to over the past few months, of course. It's not directly aimed at a single therapeutic target, but it's an idea of potential usefulness, and my employer has every right to expect me to keep quiet about it. After all, I'm using their facilities to try to make it work. So all I can do is speak in generalities for now, with the hope that if it pans out, that anyone who's interested can read about it in a patent or publication. (Of course, I do have some readers at the company itself, and they've called me up at times to ask me what the heck I'm talking about. I can ease the suspense for them, not that this stuff seems to be keeping anyone up at night besides me.)

This work is on my mind because I'm nearing another crucial set of experiments, as I alluded to on July 24th. All that remains is working out some analytical methods so I can be sure that I know what I'm looking at - and I can tell you, it's a real strain for me not to just go ahead and run the things without doing that first. I could always just put the stuff in the freezer, I mutter to myself, and when I get the analysis worked out, they'd just be there waiting for me.

But that's no way to work. It shouldn't take that much longer to have a well-controlled experiment that I can actually follow. There's another new one coming up right behind that one, and I can hardly wait to get it ready to go, too. Then it'll be time for the "nonspecific elated noises" I promised when I first had this idea (see April 28, also May 2 and May 3 if you're interested.) Or, perhaps it'll be time for some Botox-worthy furrows in my brow, as I try to figure out what went wrong and why. . .

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Close To the Vest

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Posted by Derek

Another line in one of the aforementioned Paul Orwin posts rang true for me. He was discussing some new ideas in antibacterial research, then brought himself up short as he got close to his own work: "In the highly competitive world of academic science, even a weblog is no place to divulge current research tidbits"

The same thing goes, with pistachio nuts and a cherry on top, for industrial research. I've hardly said a word about the actual work I do during the day, and I don't plan to, either. It's a pity, since it's been an interesting project with a lot of twists and turns, and it would have been a good illustration of what med-chem research is like day-by-day. But I'd have been fired long ago if I tried to do that, and rightly so. Like all other pharma companies, no one hears a word about what we're up to until we're darn good and ready to tell 'em.

That's what makes information such a strange commodity in the business. The Journal of Medicinal Chemistry("Jay-Med-Chem" to its friends) can be an interesting read, but only in a historical sense. Projects you read about there are either well along in the clinic, or well buried out back with grass growing over them. The same goes for presentations at conferences. When I see a poster from a drug company with a good crowd around it at a meeting, I always think of someone attracting birds by throwing stale bread on the ground.

I've been guilty of crowding around 'em, too, though. I've come back from meetings bursting with the latest news from other companies, as given in their presentations. But we all have to remind ourselves that these breaking headlines are like light from distant stars. Who knows what's happening there now?

This all applies to the research project that I've alluded to over the past few months, of course. It's not directly aimed at a single therapeutic target, but it's an idea of potential usefulness, and my employer has every right to expect me to keep quiet about it. After all, I'm using their facilities to try to make it work. So all I can do is speak in generalities for now, with the hope that if it pans out, that anyone who's interested can read about it in a patent or publication. (Of course, I do have some readers at the company itself, and they've called me up at times to ask me what the heck I'm talking about. I can ease the suspense for them, not that this stuff seems to be keeping anyone up at night besides me.)

This work is on my mind because I'm nearing another crucial set of experiments, as I alluded to on July 24th. All that remains is working out some analytical methods so I can be sure that I know what I'm looking at - and I can tell you, it's a real strain for me not to just go ahead and run the things without doing that first. I could always just put the stuff in the freezer, I mutter to myself, and when I get the analysis worked out, they'd just be there waiting for me.

But that's no way to work. It shouldn't take that much longer to have a well-controlled experiment that I can actually follow. There's another new one coming up right behind that one, and I can hardly wait to get it ready to go, too. Then it'll be time for the "nonspecific elated noises" I promised when I first had this idea (see April 28, also May 2 and May 3 if you're interested.) Or, perhaps it'll be time for some Botox-worthy furrows in my brow, as I try to figure out what went wrong and why. . .

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July 24, 2002

Experimental Update

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Posted by Derek

For the six or eight of you who might be wondering, the experiments that I've been talking about on and off for a few months now are back on again. (To catch up newer readers, I've been irritating folks with breathless references to an idea I've had, that I can't detail for proprietary reasons. It ends up like a demented variation of "Charades" where you don't want anyone to guess the answer.)

At any rate, I've found some more test systems that look promising, and that I can get to (chemically speaking) without working up too much of a sweat. These will be exciting to run, because I think they have a fairly good chance of working. And if they don't, that's going to put a dent, a palpable dent, in my hypothesis. Sometime in the next week or so, I'll know. posted by Derek Lowe

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May 31, 2002

In Case Anyone's Wondering

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Posted by Derek

I'm still working on the research idea I've been talking about. New data from some of my colleagues is helping out quite a bit, but it means changing the experimental design quite a bit, too. Beats flying blind, though, I have to say.

Things have moved from the blast-of-inspiration stage to the get-this-thing-to-work stage. That's a longer and slower one, where many ideas die from lack of nourishment. I'm not going to let that happen in this case - if this idea wipes out, it'll be because it just plain doesn't work, not because I didn't get around to properly testing it.

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May 12, 2002

Back for More

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Posted by Derek

No earthshattering news from the meeting (not, as you could tell from my last post, that I necessarily expected any.) I did make good use of some of the time, though, by taking a stack of scientific literature with me and (for once) actually reading most of it.

Like most researchers, too often I equate photocopying a paper (or, for the more recent years, printing off a copy of the PDF file) with reading it. This was brought home to me again as I made my way through this stack. The papers I'd taken with me are the ones that come closest to the idea that I've been (obliquely) talking about for the last few weeks. I was going over them hoping to pick up some relevant details that could help out in the next experimental tests.

That I did. I'm now convinced that the experiment I ran last week had almost no chance of actually working, and I'm almost equally convinced that I know why. (I generally find my own arguments pretty convincing, which is a mental habit that can be an equally great strength or handicap. You never really know which until it's too late, though. . .)

At any rate, I think that there's a key variable in my experimental setup that I've wrongly estimated. It'll take a few days to rearrange things to put that hypothesis to the test, but that's the next order of business. Of course, if I get everything lined up and things still don't work, I haven't proven anything. But the changes I'm making make logical sense to me (and to my other co-workers who are helping out or following along.) If things don't work this time, at least I'll feel that I've given them every chance to. And I'll be incorporating these changes in the future variations I've spoken of (the ones that, intrinsically, I think have a better chance of working.)

Whenever you change something in your experimental design, there's always a nagging fear that you're unknowingly about to abandon the only conditions that could make things work properly. In this case, the good part is that the original setup I chose is still available. It's the starting point for the new one, and I can (and will) still take data under those conditions as I go on into the new conditions.

Of course, the downside of testing things out this thoroughly is that your original idea is on the chopping block the whole time. Getting all the variables figured out, thinking through just how you want to run things - these could be just sharpening the blade. The nerve-racking thing about science is that we really do prove things. And sometimes we prove ourselves wrong. . .

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May 6, 2002

Meanwhile, Back at the Chocolate Factory

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Posted by Derek

The attempt today to put one facet of my latest ideas to the test wasn't too encouraging. I didn't get the effect that I was hoping for, but the data suggest some complications that might have intervened.

The next set of experiments is coming up soon, and I'll incorporate what I've learned this time into their design. Next time I try this particular angle, I'm going to do it with several closely related starting materials, in hopes that some of the factors that complicated today's run might clear up with changes in that aspect of the system. If they do, then it's great news. If they don't, then I can rule out some more explanations of why things are going like they are. An ideal experiment is one whose every possible outcome is full of unequivocal meaning. I can't set up one of those, but I can try to make the ones I have cut in as many simultaneous directions as possible.

I've also received an offer of assistance in the form of another analytical technique, which could prove very useful on its own and as a reality check on the others. If any of this stuff starts to work, I'll need all the reality checks I can get.

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May 3, 2002

The Nuts and Bolts of a New Idea

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Posted by Derek

Well, Monday will mark the first test of the research ideas that I've been talking about (see the 4/28 and 5/2 posts below.) It's not the perfect experiment that I'd like, partly because it'll be testing one of the less-likely forms of the idea. On the flip side, if this one works, plenty of other stuff probably will, too. I have the starting materials I need ready to go, as well, which comes under the "bird in the hand" principle.

The main uncertainty is still in the control experiments. There's a way that I could get a false positive in this experiment, and there's no way to keep that from happening. It's intrinsic. But there is a way to control for it, leaving out one key factor in a separate experiment. If that run gives me the same result as the "real" one, then I'm in trouble. It'll mean that what looks like a positive result could just be what would happen anyway. I've got several "Plan B"s to go to at that point, other experiments with different starting materials that still might show that the underlying idea could work (just not on the first thing I tried.)

If the results are different in the control versus the real experiment, though, it'll be time to break out the party hats. But I won't know that for a while yet, unfortunately. The complicated part is that I can use a fairly straightforward method to measure how things are going, but it'll only work for the real experiment, not the control. There's a more complex method that'll work for both, so that's what I'll need to do the key head-to-head comparison. It won't be ready for prime time for another week or two; I have some colleagues who are going to work on that for me.

So, Monday's experiment is just a first hurdle. Using the straightforward readout, if the real experiment shows something, that's a necessary (but not sufficient!) piece of evidence. I'll be relieved, but I won't be high-fiving anyone. If it doesn't show anything, though, I'll know to move immediately on to one of those Plan Bs I mentioned.

One of those doesn't deserve that label, actually - it's the system that I think has the best chance of all of them of showing the effect I want. But it requires some chemical synthesis, which is in progress. With any luck, I'll have the necessary compounds made at about the same time my friends in the other hallway get the robust method for comparing the experimental results. When we get that all working at the same time, we'll be ready for some serious moments of truth. Monday's, by comparison, will be a small one. But I'm excited, just the same.

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May 2, 2002

Measure Twice, Cut Once

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Posted by Derek

Not much time to post at the moment, between home life and work. If this were in my single days, I'd be at the lab until all hours working on the ideas I spoke of, but I don't think my two small children would care for that (and I'm certain that my wife wouldn't!) I give her updates on what's going on, though (we used to work at the same pharmaceutical company, and she knows the field.) Actually, I even give my 3 1/2 year old son updates: "Daddy, did you use your stir plate today?" "Yes, I did!" "Did you use your hydraulic hammer?" "My what?" "Did you use a backhoe today, Daddy?" "Um. . ."

I'm involved now in experiment design, trying to make sure that I control for all the possible explanations of what could happen. I find it useful to imagine myself explaining this stuff to the most sceptical/hostile people I've encountered in my scientific career. Picturing what questions they'd ask is a good way to come up with control experiments to make the results stronger.

It's frustrating not to immediately run and set something up, but a few days spent at this point could mean a lot. An experiment that looks like it might be big, but could also be explained by something uninteresting, is almost worse than having a negative result. With a little care up front, I can avoid that situation completely.

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