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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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In the Pipeline

« Bright Lights and Applause? | Main | Lights, Camera, Pharma! »

November 6, 2007

Andy Grove: Rich, Famous, Smart and Wrong

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Posted by Derek

So I see that Andy Grove, ex-Intel, is telling everyone that the drug industry could use some of that Moore's Law magic. I've noticed that people who spend a lot of time in the computer business often have an. . .interesting perspective on what constitutes progress in other fields, and we might as well appoint Grove the spokesman for their worldview:

Q: In what way does the semiconductor industry offer lessons to pharma?
A: I picked the semiconductor industry because it's the one I know; I spent 40 years in it, during which it became the foundation for all of electronics. It has done a bunch of unbelievable things, powering computers of increasing power and speed. But in the treatment of Parkinson's, we have gone from levodopa to levodopa. ALS [Lou Gehrig's disease] has no good treatment; Alzheimer's has none.

To me, the first sentence of that answer is the key one. As for the rest of it, hey, it's all true. Perhaps one explanation for the difference between the two fields is that they're driven by fundamentally different processes? Nah, that can't be right:

Q: Why is the speed of progress so different in semiconductor research and drug development?
A: The fundamental tenet that drives us all in the semiconductor industry is a deeply felt conviction that what matters is time to market, or time to money. But you never hear an executive from a pharmaceutical company say, "Before the end of the year I'm going to have xyz drug," the way Steve Jobs said the iPhone would be out on schedule. The heart of every high-tech executive has been, get the product into customers' hands and ramp up production. That drive is just not present in pharma; the drive to get sufficient understanding and go for it is missing.

Well. Where to begin? Let's start with a minor fact, and work our way up. I've been in this industry for eighteen years, and I cannot count the number of year-end goals I've had to deal with. Number of new targets identified, number of new projects started, number of compounds recommended for development, number of compounds progressed to Phase II, number taken to the FDA. It never ends. If Andy Grove hasn't heard a pharma executive talk about all the wonderful things that are going to be done by a given timeline, he needs to listen harder.

But here's the rough part: although drug company people talk like this, they're full of manure when they do. These year-end goals, in my experience, do very little good and in some cases do a fair amount of harm. I'll bet some of my readers have sat in a few meetings - I sure have - and looked up at the screen thinking "Why on earth are we recommending this drug to go on?", only to have the answer be "Because it's early November". More idiotic things may get done in the name of meeting year-end numerical goals than for any other reason in this industry, so thanks, but I'll try to ignore the recommendation to do them some more, but good and hard this time.

Mr. Grove, here's the short form: medical research is different than semiconductor research. It's harder. Ever seen one of those huge blow-ups of a chip's architecture? It's awe-inspiring, the amount of detail that's crammed into such a small space. And guess what - it's nothing, it's the instructions on the back of a shampoo bottle compared to the complexity of a living system.

That's partly because we didn't build them. Making the things from the ground up is a real advantage when it comes to understanding them, but we started studying life after it had a few billion years head start. What's more, Intel chips are (presumably) actively designed to be comprehensible and efficient, whereas living systems - sorry, Intelligent Design people - have been glued together by relentless random tinkering. Mr. Grove, you can print out the technical specs for your chips. We don't have them for cells.

And believe me, there are a lot more different types of cells than there are chips. Think of the untold number of different bacteria, all mutating and evolving while you look at them. Move on to all the so-called simple organisms, your roundworms and fruit flies, which have occupied generations of scientists and still not given up their biggest and most important mysteries. Keep on until you hit the lower mammals, the rats and mice that we run our efficacy and tox models in. Notice how many different kinds there are, and reflect on how much we really know about how they differ from each other and from us. Now you're ready for human patients, in all their huge, insane variety. Genetically we're a mighty hodgepodge, and when you add environment to that it's a wonder that any drug works at all.

Andy Grove has had prostate cancer, and now suffers from Parkinson's, so it's no wonder that he's taken aback at how poorly we understand each of those diseases - not to mention all the rest of them. But his experience in the technology world has warped his worldview. We are not suffering from a lack of urgency over here - talk to anyone who's working for a small company shoveling its cash into the furnace quarter by quarter, or for a large one watching its most lucrative patents inexorably melt away. And we don't suffer from a lack of hard-charging modern management techniques, that's for sure.

What we suffer from is working on some of the hardest scientific problems in the history of the species. Mr. Grove, the rest of your recommendations don't betray much familiarity with the industry, either, so there may be only one way to make you really understand this. If you really, really believe in your ideas, please: start your own company. You've got the seed money; you can raise plenty more just by waving your hand. Start your own small pharma, your own biotech. Hire a bunch of bright no-nonsense researchers and show us all how it's done. Tell them that you're going to have a drug for Parkinson's by the end of the year, if that's what you think is lacking. Prove me and the rest of the industry wrong.

Comments (86) + TrackBacks (0) | Category: Drug Development | Drug Industry History


COMMENTS

1. Bryan on November 6, 2007 9:24 AM writes...

A few minutes reading Gary Pisano's Science Business might enlighten Mr. Grove. Although I dont know how well received Pisano's later conjectures are in the book, he sums up the comparison between semiconductors and drug development quite succinctly. Changing the socket on a motherboard is a lot easier than altering a gene to modify a kinase's active site to fit your drug.

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2. PharmaProphet on November 6, 2007 9:54 AM writes...

Actually, I think one of the major problems facing the industry is that upper management is thinking and behaving *exactly* like Mr. Grove. Too much concern for the almighty $, and far too little understanding of how scientific progress really occurs.

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3. matt on November 6, 2007 9:56 AM writes...

Wow, great post. Hit the nail on the head. And by the way, what is up with acomplished old guys (i.e. Grove and Watson) saying dumb stuff lately?

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4. John Novak on November 6, 2007 9:56 AM writes...

Grove also doesn't have the FDA and medical ethics boards to contend with. (Not that he should, or the pharma industry shouldn't! But the semiconductor market, while ruthless in its own way, will not send you to jail for a poorly thought-out experiment.)

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5. matt on November 6, 2007 10:01 AM writes...

Wow, great post. Hit the nail on the head. And by the way, what is up with accomplished old guys (i.e. Grove and Watson) saying dumb stuff lately?

And also, what's up with the Neuroscience meeting? That's where Grove had the platform to say all this stuff. I hope people laughed him off the stage or at least gave him some hard zingers after his talk. And two years ago they invited the Dali Lama. Why do they even waste their money? These events sure do generate a lot of publicity, but it's already one of the largest meetings in the world. Not like they need to advertise.

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6. GA on November 6, 2007 10:19 AM writes...

Derek, I'm glad you took this on - when I first read this piece (and it seems to be getting some headlines), all I could do was shake my head in amazement. I'm sure that Andy got the "process" right at Intel, so that chip after chip gave the same performance. However what he fails to understand is that the reason why drug discovery and development fails more often than not is not because the "process" is sub-optimal or the "drive" is missing. It's because of the inherent complexity of the systems we deal with.

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7. TW Andrews on November 6, 2007 10:35 AM writes...

Wow. It's not often that you hear that the problem with drug development is that the pharmaceutical industry isn't interested enough in money.

In any case, I think the root of Grove's misunderstanding is that he confuses engineering challenges like the ones that the semi-conductor industry typically faces with the scientific challenges inherent in drug development.

When Intel started putting transistors on chips, it was well understood how electrons moved through conductive materials, and how boolean gates operated. That wasn't something that they had to develop from scratch, let alone for each chip. I guess I don't need to go into detail here on how that's different from drug development where eternal principles are few and far between.

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8. RY on November 6, 2007 10:59 AM writes...

As computer scientist who re-tooled into a geneticist/biologist a few years back, I understand exactly where Grove is coming from... and why he is so wrong. The problem with bio-medical science is that all the mess and complexity gets suppressed in the popular press (i.e. NYTimes, Economist, WSJ) and luminaries like Grove get a totally warped sense of what we know and don't know. Even the neat little diagrams of pathways we sometimes make give the illusion of knowledge and simplicity which is utterly misleading. I think, we, as a community, need to do a better job of educating other professionals and the public... (though I fear it may not be possible)

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9. Bryan on November 6, 2007 11:05 AM writes...

Just a quick question, but what do you guys think about his comments and criticism of academia and peer review? (bottom page 2 http://www.newsweek.com/id/68221/page/2)

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10. Nick K on November 6, 2007 11:45 AM writes...

Message to Andy Grove:

I'll listen to your ignorant, ill-informed comments about drig discovery if you listen to my equally ignorant, ill-informed comments about chip design.

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11. Nick K on November 6, 2007 11:46 AM writes...

Message to Andy Grove:

I'll listen to your ignorant, ill-informed comments about drug discovery if you listen to my equally ignorant, ill-informed comments about chip design.

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12. paiute on November 6, 2007 12:00 PM writes...

You forgot the most important difference:

Crashed computers = no big deal (patch it)

Crashed humans = multimillion dollar judgement

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13. excimer on November 6, 2007 12:27 PM writes...

Excellent post. I, too, shook my head in amazement at this guy's comments. There really is little to compare between the methods in the semiconductor industry and the pharma industry.

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14. TFox on November 6, 2007 12:46 PM writes...

In 40 years, Parkinson's has gone from levodopa to levodopa. The chip industry, on the other hand, has gone from transistors in silicon to transistors in silicon. *All* advancement in electronics is what pharma types call scale-up, doing the same thing you did last year a little cheaper. Scale-up, needless to say, is not the hard part of new drug development...

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15. DLIB on November 6, 2007 1:10 PM writes...

I'm a pharmacologist that works in the semiconductor industry ( across the street from Intel in Santa Clara ) the company I work for ( Brion technologies/ASML ) allows chips to be designed smaller and smaller -- 16nm lines are on our roadmap. It's true, there's no comparison in the complexity of the problems associated with the respective industries. We do computer modeling of the optical systems used to expose resist. Our models are good enough to resolve better than .5nm differences in edge placement. Just fine when printing an IC. Not good enough for Docking/scoring. The search algorithms bare some resemblance. Ours are physically based. We can fairly represent the complete system. You guys with much bigger and faster computation can't represent the system entropy change very accurately at all ( you need a real calorimeter for that ). There is cross fertilization that's possible but probably more the pharma industry could teach the Semiconductor industry.

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16. Kay on November 6, 2007 1:10 PM writes...

What if the electronics industry had Rules that did not work? What if they generated data but did not really believe the results? What if they chose to continue to use the Rules and results? What if the workers chose not to admit these faults to management?

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17. haywarmi on November 6, 2007 1:15 PM writes...

Hey Bryan, I'm glad someone else took note of that comment. I'd agree that the peer review system pressures conformity but who's going to weed out the "wild ducks" from the lame ducks? Especially tough when you're handed 20 50 page grants to review (and get paid nothing except the privilege of doing it)?

My impression is that this already exists, to a limited degree, with the HHMI and merit grant system. That is, those who have already proven themselves to be forward thinking and creative are given some license to explore. More of this, though, takes away from the deserving young investigators who may be more creative and technologically innovative.

Those who are so quick to point out that the peer-review process stifles creativity aren't always aware that the funding levels are nearing the single digits, so how do you make that decision? Its not like we have a lot of error to play with, which is exactly what you need to find (or encourage) those wild ducks. You use a shotgun to hunt ducks for a reason and right now the NIH is using a BB-gun (I'll stop with the analogies now but I didn't start it, "wild duck" came from Grove)

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18. Wavefunction on November 6, 2007 1:34 PM writes...

Actually a drug is just like a chip. You outsource its production to a third world country, you get all kinds of crap put into it, then it works for some time, develops a defect, kills its consumer in one way or the other and finally becomes obsolete.

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19. Chemgeek on November 6, 2007 1:36 PM writes...

A more blatant and ridiculous example of comparing apples and oranges I have never seen. (although, apples and oranges are more similar than pharma and chip design).

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20. SRC on November 6, 2007 1:39 PM writes...

I'm a bit shocked that Grove does not grasp the difference between science and technology.

Designing a chip is a matter of engineering, the underlying scientific principles having long since been worked out. It's more akin to the space program than to pharmaceutical research. Progress in scientific research happily ignores timelines that engineering development observes religiously, because caprice plays no role.

The better parallel would be to liken biomedical research to natives in Borneo attempting to build a computer.

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21. Molecular Geek on November 6, 2007 1:57 PM writes...

SfN has speakers like Grove or the Dali Lama in addition to the more traditional plenary speakers because part of the mission of a major meeting like this is to include discussion of the larger context of the science that the attendees are doing. They also have public lectures during the meeting to engage the communuity. As someone here at the meeting, I can say that his remarks were listed on being about "Ending the R01 Culture in research". I won't defend his position. Others have correctly called him to task for his misunderstanding of the relationship between chip design and drug design. I'm sure that in his mind, if every academic were to refocus their energies away from trying to get NIH or NSF support, and find a way to become a biotech/pharmaceutical entrepeneur, he wouldn't have to fear that prostate cancer or the onset of parkinsons. I won't go any further with this tired old canard. We see it often enough in critiques of the industry.

I would also point out that Grove was here on a panel discussing funding woes in biomedical science. As a followup to that, Newt Gingrich showed up for a plenary yesterday arguing that the refusal of the current administration to keep funding the NIH budget on its previous trajectory is shortsighted, dangerous, and wrong. (Who would have ever thought he would come out for more government spending?).

Just for context, Neuroscience 2007 is huge. There are over 32,000 attendees here, and the poster hall runs for the entire length of the convention center exhibit hall (at least 500 meters, end to end) with topics ranging from molecular mechanisms of synatogenesis and ligand design through clinical behavior studies and discussions on the physiological nature of conciousness. (The latter is the topic that brought the Dali Lama to speak a couple of years ago. I wasn't there for it, but my better half said that it was a very powerful talk, and it was SRO in the 2 overflow rooms where they simulcast the presentation). They don't have sections like the ACS meetings do, so trying to decide which talks and which posters to attend is like drinking from a hydrant. They attract good speakers that can draw interest across a very broad spectrum of attendees. If anyone else gets a chance to hear Sebastian Seung from MIT speak, do it. He spoke on Monday night, and he gave one of the best lectures I have heard. It was at a Scientific American level to make sure that it was accessible to the entire audience, but his lab had posters on the details yesterday afternoon as well.

MG

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22. CMC guy on November 6, 2007 2:02 PM writes...

This is a stimulating subject: Attempting to apply semiconductor model to pharmaceuticals does seem to be the preverbal round peg. As noted in multiple comments the complexities are vastly different. Even when we gain knowledge in areas such as mol bio and genetics the translation into acceptable drugs is a difficult pathway that isnt so straight (and paiute nails risks). I dont know how many research programs (and expense) have gone into treatments for Parkinsons and Alzhemiers since the 1950/60s (timeframe in Grove article?) but would suspect numerous approaches explored and perhaps even a few made to clinical trials.

Although at times it seems Pharma has bought into fundamental “time to money” principle at the core think most people doing the work so that will benefit sick people and have to delicately balance efficacy with ill effects. Unfortunately what works in animals often proves unsuitable for people so crossing gulf between demo a cure for a cancer in a mouse and the advancement to human the bridge collapses. Grove mentions biomarkers lack of emphasis but how many times have we seen compounds give excellent responses based on such but still fail to do the job against the disease (see PSA for Prostate Cancer for example).

Grove does have interesting comments about “conformity of thoughts and valves” (targeted academia mainly) which I do see as a problem in Pharma with too few companies willing to move off save territory. More innovations/wild ducks are needed to solve illnesses but that will not come unless the funding opens to enable these novel explorations and the short-term ROI view that now dominates investors drives to only immediate high return results.

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23. Ian Ameline on November 6, 2007 2:09 PM writes...

All the comments here are quite good, and I agree with them, but another component of why chips are "easier" than cells is that the designers of each generation of processors are using the previous generation as tools to make the next. There is a positive feedback loop in there that just doesn't exist in Derek's world.

This is not necessarily true of the lithography equipment used to manufacture the chips, or the materials science that goes into making the precise compounds that form the transistors -- but on the whole, it is just so many orders of magnitude more predictable and understandable than the processes that take place in a cell that I'm quite sure I don't grasp even a part of why Derek's field is so much harder than mine...

Keep at it Derek and colleagues -- we're all getting older, and sooner or later we're all going to depend on the fruits of your labor for our continued survival.

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24. Ai yi yi on November 6, 2007 3:07 PM writes...

There seems to be a pretty unanimous opinion here, and I voice my agreement as well. The refinements in chip design are more akin to developing a new formulation of an existing drug - perhaps a syrup for children, or a controlled release version, etc. Those are the types of refinements that the pharma industry can realistically achieve within a set time period, and accurately forecast the effort and costs involved, and they are more on a par withthe incremental advances in chip design. So did he give a timeline for when the electronics industry will finish building that Star Trek transporter? At least that would make those trips to the doctor more convenient............

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25. MTK on November 6, 2007 3:44 PM writes...

OK, there's a concensus here, so let me throw a couple of things out there. One intentionally provocative, and tongue in cheek, and the other a bona fide question.

a) If one looks at total R&D spending vs. R&D spending as a % of sales, the electronics industry leads the former, while the pharma industry leads the latter. So if Andy Grove wants the pharma industry to become as incentivized, and as fast, as the semi-conductor industry, one conclusion is that mandatory government price controls, floors not ceilings, be instituted. That would do it, right? Companies would make damn sure that stuff got done if there was guaranteed greater than market value return.

b) If Pharma can't learn from the semi-conductor industry, what industries can it learn from? I find it highly self-patronizing to think that we're so special and so difficult that we can't apply some principles from other successful industries, countries, or segments. I'm just not sure what they may be.

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26. qetzal on November 6, 2007 3:57 PM writes...

I can easily forgive Grove for not understanding why pharma is fundamentally different from the semiconducter business. I can even forgive him for not understanding that pharma is fundamentally different.

But if he honestly thinks pharma's problem is not enough drive to bring product to market, he's being an idiot. You don't have to understand pharma to know better than that. You just have to understand the tiniest bit about business.

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27. Jose on November 6, 2007 4:18 PM writes...

MTK- I think that realizing pharma *is* fundamentally different from any other industry is not self-aggrandizing or indulgent, it is the *reality." Pharmacueticals are not normal consumer products!

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28. SRC on November 6, 2007 5:47 PM writes...

Jose, actually, if I had to choose a similar industry based solely upon business model, it would probably be wildcatting for oil (albeit without the FDA, or personal injury lawyers).

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29. Great Molecular Crapshoot on November 6, 2007 6:26 PM writes...

There are some who say that pharmaceutical research needs to learn from semiconductor MANUFACTURING. Lots of talk about lean stuff with lots of beancounting and statistics, communicated with religious zeal. Nobody seems to notice that the pharmaceutical industry might be a little more regulated than the semiconductor industry. Let's also remember when the secretary of defense was recruited from General Motors and look where that ended up.

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30. Great Molecular Crapshoot on November 6, 2007 6:33 PM writes...

OK so it was Ford and not GM; hope everybody spotted the mistake.

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31. Ian Musgrave on November 6, 2007 6:39 PM writes...

Bravo, a truly excellent post Derek.!

But in the treatment of Parkinson's, we have gone from levodopa to levodopa.
(coughs politely) Well, in Australia it's levodopa plus dopadecarboxylase inhibitors (as this greatly reduces side effects), no one prescribes levodopa alone. Not to mention amantidine (okay, so it doesn't work so well, but has fewer side effects) and bromocriptine. In those 40 years we have tuned doses, added drug combinations (levodopa, MAO inhibitors and DDC inhibitor combinations work best), and tried out a heap of things that just didn't work.

But what does he expect? In Parkinsons (and Alzheimer's and ALS), brain cells are dying. You can't bring back brain cells once they are gone. We have only a limited idea of why they die, and virtually no idea of how to stop them dying. Until we know mechanisms in more detail, anything we do is palliative only (levadopa helps the few remaining brain cells make more dopamine, when they finally die off, levadopa stops working). Rushing drugs to market is pointless when we don't know the mechanism of the disease. I speak here as someone who is trying to develop drugs to unravel beta amyloid, which is most likely the major pathogenic event in Alzheimer's (but maybe it's not). With Parkinson's we are even more in the dark (alpha synuclein anyone?).

Stopping brain cells dying, or replacing them, is a seriously hard problem (remember the big hoo-ha about neural cell transplantation in the late 90's, it ended up not working).

Making transistors which fit more elements on a chip is a significant challenge, but when you make a chip you know it works almost straight away. When you get a drug working in a test tube, it will be years before you know if it works in a human (and this is doubly so for diseases like Alzheimer's where you have to wait a least a year for a knock-in animal model which doesn't exactly mimic the human disease to give you any results, let alone monitoring cognitive decline in humans).

Even if you get something that works in humans, you can't rush a drug to market in the same way you can a transistor, there's this thing called the FDA (or the TGA in Australia, and the UK and European equivalents). Also, new chips aren't likely to kill people because of a rare gene polymorphism that isn't picked up on the initial tox scan.

But still and all, if you don't know the mechanism of the disease, then useful treatments will be hard to come by. And as Derek and other have pointed out, biology is complex, finding drugaable answers is a ling hard row to hoe.

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32. srp on November 6, 2007 6:47 PM writes...

In the spirit of devil's advocacy, I'll try to come up with some sense in which Grove might have half a point. I agree with the consensus above, but Grove's critique stimulates some heretical thoughts. And let me say in advance, I'm aware of the various institutional barriers to the suggestions below; but if these suggestions have some merit, then changes in those institutions would be the next order of business.

1. At Intel, and I believe at most semiconductor companies, there is very little emphasis on developing fundamental first-principle knowledge about why things work. Instead they just try to get them to work, record what they did that got them to work, and go from there.

My understanding is that pre-"rational"-drug design, the pharma industry worked the same way and generated a lot of useful drugs with high research productivity compared to today. Is there any evidence that intentional targeting of receptors is better than blind screening (based on hunches) at turning up good drugs? And if such evidence is absent, does it make sense to cling to a research model that increases emotional comfort but reduces average research productivity?

2. A weak analogy to the uncertainty of how a drug will work in a human is provided by the uncertainty of how a new semiconductor device or process technology will work on a production fab. (I realize that the uncertainty is a whole lot less, but bear with me. The difference actually works in favor of my argument.) The semiconductor folks build pilot lines and try to test in a realistic environment as quickly as possible, because the actual fabs are extremely complex and finicky systems (as human artifacts go). Stripped-down or simpler analogues to a real production line can be misleading models for what will happen when you try to do something for real at commercial quantities.

In drug research, we have a really complex and finicky environment--the human body--but a lot of time is spent working on animal models. From previous posts by Derek, I infer that there is no systematic evidence that success in animal models is highly correlated with success in people, or even that animals are really easier to cure than people. It seems to be an article of faith rather than a scientific principle that if something doesn't work in rats, it won't work in people (we know for sure that the inverse statement is false from all the rat cures that fail in human trials). Maybe getting compounds into humans earlier, faster, and more frequently and using animals less intensively is the key to getting more actual drugs into the marketplace.

Obviously, these are not airtight arguments, just ideas that Grove's analogy stimulated. How much of the standard operating procedures of pharma research is grounded in evidence that it really improves research productivity?

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33. StW on November 6, 2007 8:49 PM writes...

Reading all these comments, one might think that our basic medical research and clinical research systems are working as well as they possibly can. An objective look, however, would not produce