We're all pretty specialized in this business. And since you know your own field well - well, you should - then you have a good idea of what its strong and weak points are. But do you know what they are for the other areas you deal with? If your only exposure to some other field is listening to people make presentations about it, then you probably have no idea. Outside presentations almost invariably exist to make everything look as if it's going perfectly, with wisdom and insight flawlessly translated into action. (Don't believe me? Go back and look at some of your own slides, then get back to me).

No, to really understand a specialty, you have to go do it yourself. But if that's not an option, the next best thing is to know the people involved well enough to watch them work (and to hear them complain). If you're a relatively high manager, though, this will most likely never happen. Not that you won't be able to hang around the lab; you can, if you want. But the people there probably won't open up enough to let you see how things are really going. That's because things are going the same way that they're going everywhere else: by fits and starts, with false starts and wrong turns, and with the usual quota of human bungling. How could it be otherwise? And who wants the boss to get a detailed look at it?

So mistakes are papered over, but at the same time, routine successes are often made to look special. It won't do to have people think that too much of your work is easy and routine. Someone's then likely give you lots more of it, for one thing, and what do you do when something doesn't go as planned? "Hey, you know that easy stuff that we pretty much always get right? Well, guess what?" No, that's not going to go well. Better if people who aren't trained in your field have a somewhat exaggerated idea of its difficulty. (And since you never know when things are going to turn difficult, it's good practice to behave as if they generally are).

As an organic chemist, I'm willing to spill the beans on a few of our own secrets. Here's one: the bulk of the reactions we run are pretty standard stuff. That's no accident. We go to a lot of trouble to make things come out that way, because when we get into nonstandard stuff there's no telling what might happen, or how long it might take. Keeping as much of your chemistry as possible on the well-trodden paths is a form of productivity insurance. And don't let anyone kid you: compound productivity is really important, because we don't know enough to pick the One Perfect Compound to make.

So we make a lot of compounds. We make them with as much thought as possible about where to start and where to go, but still, the more, the better. That means we prefer good ol' reliable reactions, like the ones Momma used to run. This bias for boring chemistry is something that chemists fresh from academia have to get used to. The mental adjustment lies in realizing that chemistry is just a means to an end - a drug! - and that the fastest, easiest, and most reliable means are the best. If they're boring, well, fine. Note that I'm talking about the chemical steps needed, not the structures that result from them. Those need to be unique in some way, of course, if they're to be patented. But you can make a lot of previously-unknown structures (millions of them) using nothing but reactions that sophomores learn in their first organic chemistry course.

That's our secret - well, it's one of our secrets. One of the others is that we generally make more compound (or try to) than we think we're going to need, but I'm afraid that this one got out many years ago. I've seen departments where the biologists asked for a lot more compound than they really had to have, because they knew that the chemists would complain, but then felt relieved when the amount required went down. And besides, they assumed that the chemists probably had some extra stuff hidden away. But for their part, the chemists assumed that the biologists were exaggerating. They'd have to be, wouldn't they, because who could ask for such insane amounts of final compound, unless someone had switched to doing two-week tox in rhinos? So the chemists didn't get too worked up if they delivered a bit less than planned, and the biologists didn't get too worked up, either, because it was still more than they needed. Not the most efficient way to run things, you'd think, but it seemed to work.

What about the secrets of other disciplines? As for molecular biology, I'd have to say, as an outsider, that one of the key features of it is that it's using tools that are incredibly well optimized to do what they're supposed to do. I mean, cells want to divide, enzymes want to pick up their substrates, DNA's there to be read off. That's the single biggest difference compared to organic chemistry, because our reagents are pretty blunt tools compared to something as impressive as PCR. Of course, the biologists are forever trying to make these tools do more than they're used to, and it's for sure that a lot of these reagents (and their products) are rather delicate things to work with. But being able to come along after a billion years of evolutionary fine-tuning really does help.

To tell the truth, I'm not sure if this qualifies as a trade secret of the field, since I wonder how many molecular biologists stop to realize it themselves, but to a chemist it does stand out. That makes me wonder what features of my own field are obvious to other people, but not to me. Do I really want to know? Look at a department like HR: I mean, to a scientist, one of the things that's immediately apparent is that there's almost no data to back up most of the things that come out of that area. Managerial fads, to be sure, often come in with impressive-looking charts showing the potential improvements. But when you look closely, you find that the categories are either non-quantifiable, or that the numbers themselves are fairly squishy.

But I've never been sure how many people in HR know this. After all, these are the sorts of numbers that they're used to, so they probably don't seem strange at all. No, I can't imagine someone looking over the latest set of wall posters they've ordered up announcing the new Seven-Sigma Vision For Team Excellence and thinking, "Gee, I hope no one realizes that this stuff isn't really backed up by anything."

No, I think that they really believe. Not having the data is a worry that those of us in the science end of things have to deal with. We know what numbers would convince us, and we know, deep down, if we don't quite have them. And that's a secret that no one wants to admit!

In the Pipeline – Six Sigma in Drug Discovery?

I had an interesting email about a 2009 paper in Drug Discovery Today that has some bearing on the "how much compound to submit" question, as well as several other areas. It's from a team at AstraZeneca, and covers their application of Lean Six Sigma to the drug discovery process. I didn't see it at the time, but The title probably made me skip over it even if I had.

I'll admit my biases up front: outside of its possible uses in sheer widget-production-line settings, I've tended to regard Six Sigma and its variants as a buzzword-driven cult. From what I've been able to see of it, it generates a huge number of meetings and exhortations from management, along with a blizzard of posters, slogans, and other detritus. On the other hand, it gives everyone responsible a feeling that they've Really Accomplished Something, which is what most of these managerial overhauls seem to deliver before - or in place of - anything concrete. There, I feel better already.

On the other hand, I am presumably a scientist, so I should be willing to be persuaded by evidence. And if sensible recommendations emerge, I probably shouldn't be so steamed up about the process used to arrive at them. So, what are the changes that the AZ team says that they made?

Well, first off is a realization that too much time was being spent early on in resynthesis. The group ended up recommending that every lead-optimization compound be submitted in at least a 30 to 35 mg batch. From my experience, that's definitely on the high side; a lot of people don't seem to produce that much. But according to the AZ people, it really does save you time in the long run.

A more controversial shift was in the way that chemistry teams work. Reflecting on the relationship between overall speed and the amount of work in progress, they came up with this:

Traditionally, chemists have worked alongside each other, each working on multiple target compounds independently from the other members in the team. Unless managed very carefully by the team leader, this model results in a large, and relatively invisible, amount of work in progress across a team of chemists. In order to reduce the lead time for each target, it was decided to introduce more cooperative team working, combined with actively restricting the work in progress. The key driver to achieve and sustain these two goals was the introduction of a visual planning system that enables control of work in progress and also facilitates work sharing across the team. Such a visual planning system also allows the team to keep track of ideas, arrival of starting materials, ongoing synthesis and compounds being purified. It also makes problems more readily recognizable when they do occur.

We have reflected on why chemistry teams have always been organized in such an individual-based way. We believe that a major factor lies in the education and training of chemists at universities, in particular at the doctoral and postdoctoral level, which is always focused on delivery of separate pieces of work by the students. This habit has then been maintained in the pharmaceutical industry even though team working, with chemists supporting each other in the delivery of compounds, would be beneficial and reduce synthesis lead times.

OK, that by itself is enough to run a big discussion here, so I think I'll split off the rest of the AZ ideas into another post or two. So, what do you think? Is the "You do your compounds and I'll do mine" style hurting productivity in drug research? Is the switch to something else desirable, or even possible? And if it is, has AstraZeneca really accomplished it, or do they just say that they have? (Nothing personal intended there - it's just that I've seen a lot of "Now we do everything differently!" presentations over the years . . . ) After all, this paper is over a year old now, and presumably covers things that happened well before that. Is this how things really work at AZ? Let the discussion commence!

Comments to this post can be found at bit.ly/c1Gwlj from http://pipeline.corante.com/ on 9/16/10
Copyright Derek Lowe, 2010

Derek B. Lowe has been employed since 1989 in pharmaceutical drug discovery in several therapeutic areas. His blog, In the Pipeline, is located at http://www.corante.com/pipeline and is an awfully good read. He can be reached at derekb.lowe@gmail.com.