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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 19, 2010

Not The End. Not At All

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Posted by Derek

All right, given the way things have been going the last few years, it's easy to wonder if there's a place for medicinal chemistry at all - even if there's a place for drug discovery. There is. People are continuing to get sick, with diseases that no one can do much about, and the world would be a much better place if that weren't so. I also believe that such treatments are worth money, and that the people who devote their careers to finding them can earn a good living by doing so.

So why are fewer of us doing so? Because - and it needs no ghost come from the grave to tell us this - we're not finding as many of them as we need to, and it's costing us too much when we do. That's not sustainable, but drug discovery itself has to continue. We can't go on, we'll go on. But what we have to do is find new ways of going on.

I refuse to believe that those ways aren't out there somewhere. We do what we do so poorly, because we still understand so little - I can't accept that this is the best we're capable of. It won't take miracles, either. Think of the clinical failure rates, hovering around 90% in most therapeutic areas. If we only landed flat on our faces eight out of ten times in the clinic, we'd double the number of compounds that get through.

I think that we're in the worst stage of knowledge about disease and the human body. We have enough tools to get partway into the details, but not enough to see our way through to real understanding. Earlier ages were ignorant, and (for the most part) they knew it. (Lewis Thomas's The Youngest Science
has a good section on medicine as his own father practiced it - he was completely honest about how little he could do for most of his patients and how much he depended on placebos, time, and hope). Now, thanks to advances in molecular and cell biology, we've begun to open a lot of locked boxes, only to find inside them. . .more locked boxes. (Sorry about all these links. For some reason literature is running away with me this morning). We get excited (justifiably!) at learning things that we never knew, uncovering systems that we never suspected, but we've been guilty (everyone) of sometimes thinking that the real, final answers must be in view. They aren't, not yet.

Pick any therapeutic area you want, and you can see this going on. Cancer: it starts out as dozens of dread diseases, unrelated. Then someone realizes that in each case, it's unregulated cell growth that's going on. The key! Well, no - because we have no idea of how unregulated cell growth occurs, nor how to shut it off. Closer inspection, years and years of closer inspection, yields an astonishing array of details. Growth factor signaling, bypassed cell-death switches and checkpoints, changes in mitotic pathways, on and on. Along the way, many of these look like The Answer, or at least one of The Answers. Think about how angiogenesis came on as a therapeutic idea - Judah Folkman really helped get across the idea that some tumors cause blood vessels to grow to them, which really was a startling thought at the time. The key! Well. . .it hasn't worked out that way, or not yet. Not all tumors do this, and not all of them totally depend on it even when they do, and the ones that do turn out to have a whole list of ways that they can do it, and then they can mutate, and then. . .

There, that's where we are right now. Right in the middle of the forest. We know enough to know that we're surrounded by trees, we know the names of many of them, we've learned a lot - but we haven't learned enough yet to come out the other side. But here's the part that gives me hope: we keep on being surprised. Huge, important things keep on being found, which to me means that there are more of them out there that we haven't found yet. RNA! There's one that's happened well in the middle of my own professional career. When I started in this business, no one had any clue about RNA interference, double-stranded RNAs, microRNAs, none of it. All of it was going on without anyone being aware, intricate and important stuff, and we never knew. How many more things like that are waiting to be uncovered?

Plenty, is my guess. We keep pulling back veils, but the number of veils is finite. We're still ignorant, but we're not going to remain ignorant. We will eventually know the truth, and it'll do what the truth has long been promised to do: make us free.

But we don't have to wait until we know everything. As I said above, just knowing a bit more than we do now has to help. A little more ability to understand toxicology, a better plan to attack protein-protein targets, more confidence in what nuclear receptors can do, another insight into bacterial virulence, viral entry, cell-cycle signaling, glucose transport, lipid handling, serotonin second messengers, bone remodeling, protein phosphorylation, immune response, GPCR mechanisms, transcription factors, cellular senescence, ion channels. . .I could go on. So could you. The list is long, really long, and any good news anywhere on it gives us something else to work on, and something new to try.

So this is a rough time in the drug industry. It really is. But these aren't death throes. They're growing pains. We just have to survive them, either way.

Comments (70) + TrackBacks (0) | Category: Drug Industry History | Who Discovers and Why


COMMENTS

1. anchor on August 19, 2010 9:28 AM writes...

Derek: So, your point is that "tough time never lasts" but "tough people do", right? The fact of the matter is people have been “toughing” for too long to be optimistic! Meanwhile, the bleeding still continues and I see no end to it. I believe that this is a “programmed tragedy” for the medicinal chemists. The pharmaceutical industry is cutting its knees and no sugar coating there.

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2. Mark on August 19, 2010 9:32 AM writes...

That's the exciting thing about working in this industry, it never stops changing.

I guarantee that whatever the next huge leap in the treatment of disease is, it won't be what everything think it will be.

Mark

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3. Anonymous on August 19, 2010 9:54 AM writes...

The tragedy, of course, is that by the time the industry recovers all the people that are "surviving" now will have moved on to other areas and be unemployable as med chemists.

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4. Ross on August 19, 2010 9:55 AM writes...

Make your mind up Derek. One minute it's all hopeless, and the best we can expect is either very modest progress against cancer, or none at all; now this piece of fluff. It just smacks very much of being a plea for the continued existence of massive pharmaceutical companies and little else. Rather like those tin rattling adverts for cancer research which without a hint of irony state...

'the research must continue'

And I suppose from their perspective it must. They wouldn't want to do anything fiscally damaging that might obviate the need for a perpetual cycle of research, that simply wouldn't do.

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5. FMC on August 19, 2010 10:07 AM writes...

I couldn't agree more with "Anonymous". Derek what you are writing sounds all great and fluffy, fact is though it does not help at all the thousands of people laid off; be it either in the US or Europe - as has been written already lot's and lot's of times on this blog. The current job market as a matter of fact is not a good advertising ground for even thinking about taking up pharma related science jobs creating therefore some sort of vicious circle as the talent pool inevitably will go down.
So what I can agree with, though, is the need to change the business of making pharmaceuticals, starting maybe with making the big wigs a little more accountable.

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6. barry on August 19, 2010 10:13 AM writes...

That 90% failure rate in the clinic has several components. One big component is our ignorance (Is blocking gamma secretase a good/tolerable thing? Will this new antibiotic make food taste so bad that no one will comply?...) Another component of that failure rate is compounds that never deserved to go into the clinic. Someone had a quarterly goal to meet, so his/her group advanced a compound into the clinic, as promised. Someone was cultivating a collaboration, so a compound was pushed forward even though it wouldn't validate/invalidate the target in question.
Making the decision to spend the cost of a Clinical trial on Scientific, rather than Business grounds won't cure all that's wrong with Pharma, but it will make the difference between that 90%failure rate and an 80% failure rate--doubling the number of successes.

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7. nase on August 19, 2010 10:27 AM writes...

Wir müssen wissen
Wir werden wissen

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8. Thomas on August 19, 2010 10:37 AM writes...

The large pharma company I 'retired' from several years ago had a 1% clinical success rate. I suspect this was overstated (i.e. a lie) but even if true clearly not sustainable for more than a generation. Until we return to the absolute basics, back to seeking the Truth only then will the Truth set us free and we will prosper once more. Until then we will continue the downward spiral. How far will we go before we realize this and take action?

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9. Resveratrol Receptor on August 19, 2010 10:39 AM writes...

I was taken with Steve McKnight's approach in his recent Cell paper where they infused 1000 compounds at 10uM each into the mouse brain, looked for a neurogenesis phenotype, and worried about the target post hoc. This kind of approach is probably more appropriate given our barbarous understanding of biology, and is certainly better than going after whatever target academic blowhard X is certain causes disease Y.

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10. Anonymous on August 19, 2010 11:00 AM writes...

Quit kidding yourself.

Med chem is dead and gone. What we're seeing today are its last death-spasms before it vomits up the rest of the useless workers still clinging the shriveled husks of these ailing companies.

Chemistry had its chance, and failed. There'll be no more money for this stupid, toxic approach toward disease treatment. Chemists are useless now. Suck it up, change tack, or get out of the way.

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11. DannoH on August 19, 2010 11:29 AM writes...

I would argue that Chemists are not and will not be useless in the context of the Pharmaceutical industry, and that there are jobs for Chemists out there. Look into any manufacturing facility, and there will be a QC Lab that needs good people.

Is it as glamorous as drug discovery? No. Does it keep you out of the unemployment line and in touch with industry? Yes.

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12. medicamenta vera on August 19, 2010 11:45 AM writes...

Hey Barry (@6):
When I was at Pfizer (RIP) Ann Arbor the end-of-the-year push for upper management to meet quotas was great because it actually allowed some worthwhile drugs to make it into the clinic. Many of the in vitro and virtual screens to triage compounds, and the stop light analysis made upper management even more brain dead.

One example of this that I lived through was a backup compound my project team proposed as a clinical candidate (CAN). The computer-based projections indicated that it would not have sufficient oral bioavailability. However, the in vivo data in rats and dogs were respectable. Clin Pharm and drug development were very unhappy, but we got the CAN in December in time to contribute to Rod Mackenzie's bonus. The human PK was excellent, so "in vivo vertitas" and thank goodness for quotas making management grow some chest hair.

With regard to Derek's post today, Big Pharma management has shown that they consider scientific staff to be a disposable commodity... when they are in a good mood. Additional understanding of biological principles is not going to right this Exxon Valdez.

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13. KMP on August 19, 2010 11:49 AM writes...

Idea 1: There is reason to be hopeful about the future of drug discovery (with a role for medicinal chemists).

Idea 2: There is currently an oversupply of medicinal chemists.

These two ideas are not mutually exclusive. The cynicism expressed in reaction to Derek's post is as irrational as Kurzweil's optimism.

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14. Hap on August 19, 2010 12:04 PM writes...

I have to wonder how the industry will recover if they keep laying off the people who might figure out the things that will make it work again. Gov't research is fine as a career if the taxes are present to sustain them, which they probably won't be. The flow of chemists to fill university grants probably won't be sustainable if people can see the writing on the wall and figure (hopefully) that long-term unemployment isn't enough of a benefit for five years in grad school and some more time as a postdoc. I can't see med chem going away (magic isn't a viable method for maintaining health or curing disease, and biologics are hard to modify), but if you can't make a living doing it (and cryogenic hibernation isn't an option) then the drug companies or their inheritors will have to rebuild it from scratch when they need its skills again, which seems sort of wasteful and self-destructive.

More generally, there seems to be a cost to getting a Ph.D. and advanced education in any area, because it precludes employment in any related field (companies don't want to pay if you can't produce right now, don't particularly want to train people, and even if they train at a lower wage, know that eventually their employees will want to be paid). If there's a high enough cost to learning, particularly in the presence of alternatives, why do companies and society believe that people will continue to engage in it (or at least, on the scale to sustain their businesses and society)?

I thought that analytical people (other than perhaps Ph.Ds) were not well paid and that the field had enough people to make security nonexistant (at least as much as anywhere else). Is that inaccurate, or overgeneral?

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15. milkshake on August 19, 2010 12:08 PM writes...

drug discovery in pharma does not work because the research culture got infested and overrun by the parasites. The infection is contagious and industry-wide.

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16. myma on August 19, 2010 12:15 PM writes...

In other words, there are known knowns, known unknowns, unknown knowns, and unknown unknowns, and we are kidding ourselves about how many known knowns we actually know.

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17. thomas on August 19, 2010 12:19 PM writes...

Believe it or not this actually happened recently.

Observation made by big pharma head honcho: 1% clinical success rate acheived by synthesizing x number of compounds.

Stated desired result: Increase clinical sucess by 100% to 2%.

Solution: Obvious. Increase number of compounds 2x (i.e. if 1% acheived by x then 2% by 2x).

Action: Immediate increase in numbers of compounds by each site to exceed 2x level.

Result: Short term; everyone writes goals to increase productivity 100% (blood out of the turnip approach).
Slightly Longer Term: Big Pharma company buys yet smaller pharma company (prey), fires non-essential and / or trouble-making employees, CEO and buddies lauded ( keep jobs) and the downward spiral continues. And continues.

Suggestion: Manditory critical thinking skills class for everyone. Let's start arguing from first principles of logic including learning the cul de sacs and see if that will help. But it's probaly too late.

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18. befuddled on August 19, 2010 12:20 PM writes...

I agree (I think) with Milkshake. Management in pharma seems to oscillate between "we must invest in new trend" (often by acquiring a biotech a la Sitris, or genomics companies in previous years) and "we're not successful enough so we must cut costs". There seems to be little stomach for the long, hard, uncertain slog that is drug development in either management or Wall St.

So globally, drug development may not be dead, but it's dying in the US.

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19. Hap on August 19, 2010 12:21 PM writes...

The Black Plague ended up (at least potentially) helping to generate a lot of our cultural and intellectual background, and in that sense, probably could be considered a good thing. However, that didn't particularly help the many who died. In some cases, human nature meant that the people who exhibited appropriate humanity were the first to go - survival didn't correlate with one's humanity or qualifications, although sometimes was improved by a lack of them. People just died, in large numbers, and whatever good that came of it, did not help the dead, or correlate with their humanity.

An oversupply of med chemists doesn't necessary mean that any culling of the herd is good. It's usually not good for a lot of it, but that harm is not a reason for it not to be good. If the culling favors the least competent, however, then the expectation that the results of the culling will be good requires blind faith that seems to be unmerited.

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20. Anonymous on August 19, 2010 12:42 PM writes...

I think at least part of the problem with Derek's analysis is that there is an assumption that there actually IS a big breakthrough waiting to be made. Surely the big lesson from the push to "Cure Cancer" is that it ISN'T one disease. The anguish for those of us who work in the field is that there is no unifying target that allows us to reduce it to one problem rather a mass of targets, none of which are expressed sufficiently in the cancer population to be economically viable for us to approach. And we may yet find that neurodegenerative disorders fall into the same category.

Perhaps we have to start to realise as life expectancy continues to surge upwards in the Western world heading towards 90 years, that perhaps, just perhaps, we have already done as much as we can in many disease areas. And perhaps, we have done more that it is economically viable to sustain.

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21. Great Molecular Crapshoot on August 19, 2010 12:46 PM writes...

While these may not be Pharma’s death throes, they could be the death throes of Pharma as we know it. I see Drug Discovery dying a death by a thousand cuts rather than imploding in a spectacular Götterdämmerung. We’ll get to the point where certain diseases are, like Malaria and Chagas, seen to be uneconomic targets for therapeutic intervention. This may prove to be due to difficulty running meaningful clinical trials or a reluctance of insurers and/or government-financed health services to fund treatments with very high per-patient costs. Big Pharma will continue to get bigger but the M&A activity that leads to this will not conserve mass and Drug Discovery scientists will be disproportionately affected. As fewer new drugs come through the pipeline, Big Pharma will start to stray into territory currently occupied by Generics. Concerned citizens will write solemn letters to their congressmen, members of parliament and newspapers demanding that something be done and governments will say, “We fixed the banks and we simply haven’t got any money left. We could always raise taxes...”

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22. partial agonist on August 19, 2010 1:06 PM writes...

Developing biologicals as drugs has really put the squeeze on small molecule chemistry as being a viable drug discovery prime asset over the past decade, but we are seeing so many failures or just marginal successes with these so-called magic bullet biologicals that I am at least hopeful that this fad will begin to reverse itself somewhat. This has been as big a pressure on us as the outsourcing issue, I feel.

By the the time it turns around, though, we American medicinal chemists may all be patent lawyers, science teachers, owner-operators of Christmas tree farms and minigolf courses, or asking people if they want fries with their order (I kid, I kid...).

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23. Karen on August 19, 2010 1:09 PM writes...

I think the question isn't "is medicinal chemistry going to continue". I think it will, in some form or another. The question is how many people will be doing it, who will they be and where will they be. The answer to that is probably not "lots of chemists at big pharmaceutical companies in the US", at least not in the near future. The answer may be "in academia" although it's unclear where all the worker bees will come from. The answer may be "in small companies that only stay in business for a year or two and then go under" which means it's also unclear whether talented people will be willing to work under those conditions. It may be in small labs funded by non-profit organizations. Or it may be in China or India or elsewhere.

However, I don't think any of those answers make me want to head back into the lab, or encourage people to study chemistry unless they're willing to have an unstable, poorly paid career that may end abruptly any time.

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24. Anonymous on August 19, 2010 1:22 PM writes...

It's not the end if we start working smarter instead of only harder. Fewer, well thought out compounds that answer specific questions and/or follow specific trends in SAR. This is how we begin to bring down cost. The old adage of 'making everything and seeing what sticks' approach (Shot-gun med chem) is not the answer to bring down costs. Fewer-smarter-compounds

This is only achieved by utilizing classical medicinal chemistry techniques (QSAR, Topliss-tree, structure based approaches, etc).

Big pharma wanted to continue to higher the total synthesis guys instead of those taught traditional med chem skills from med chem departments . Now they must reap what they sow.

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25. Skeptic on August 19, 2010 1:22 PM writes...

The 1% and 5% top wealth brackets didn't get there by participating in the labor market, but instead by owning capital. The fool who said chemistry will keep you out of the employment line failed to recognize what employment today is all about:

Employment = Debt Slavery to International Bankers

So if a listeria filled ham sandwich is your grand objective in life then organic chemistry might be worthwile putting on a resume but its about as valued to employers as elementary algebra.

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26. Great Molecular Crapshoot on August 19, 2010 1:39 PM writes...

Anonymous #24, If you think QSAR represents 'smarter' you should (a) Read The Crapshoot or (b) Have your psychiatrist prescibe some strong medication.

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27. Anonymous on August 19, 2010 1:41 PM writes...

I read the "Crapshoot" and I 100% disagree with it. You must understand QSAR to realize its value.

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28. Great Molecular Crapshoot on August 19, 2010 1:51 PM writes...

You must also understand QSAR to see the problems of over-fitting, uneven occupation of chemical space, correlated descriptors and black boxes like neural nets (where you often can't even tell how many degrees of freedom the model has).

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29. Another Anon on August 19, 2010 2:00 PM writes...

Nice attempt at cheerleading for the med chemists, Derek. Can see pom-poms pumping, as you design schemes in stitching together new molecules, contemplating new technologies.

Unfortunately, you did not include many changes outside of basic scientific observations and discoveries that are changing in our world of today, many of these you have noted quite clearly in your previous postings. Changing regulatory expectations, greater costs to running clinical studies, lack of good extrapolation abilities from animals to humans, higher safety standards with more transparency being demanded by the public, irrelavent distractions, too much hype and advertising given to biotechs, VCs, etc who have never successfully progressed a single compound to a drug.

Yes, there will be new information that will come about, some by good scientific method, some by accident, some by serendipity, which will contribute to paths toward new, successful drugs. But, the days of simply throwing more chemistry at a problem to get it over a hurdle are over for many of today's therapeutic areas. Much of the problem lies in the uncertainties of underlying biology, and as a colleague has said to me many times, biology is messy. This is not a concept that often goes down well to med chemists, who tend to like clean precise order in the world....but it is more true than not. Take the world of PPARs, Derek, which you have commented on several times. If nothing else, the one thing we can say that has been learned over the past decade on PPARs is that the area is messy! And, despite the recognition that the PPARs are involved in many interesting and facinating biological systems, we still do not know how, or even if, there is a legitimate drug target lying therein. What is the problem? The target(s) themselves? Lack of specificity of the compounds? Cross talk in the downstream signalling pathways? Or simply, the underlying unified basic biology? Biology is messy.

We can't all continue to work on new meds to lower blood pressure, where animal models are easy, and predictive to humans. Yet, new drugs must be driven from an understanding of underlying biology and biochemistry. Yesterday's approaches, with dominance through the eys of the med chemist will continue to spawn fewer successes compared to those in the past 3 decades. The clock will not turn back. It is time to adjust to the new future. Steam powered paddle boats no longer dominate traffic on the Mississippi River. Phone land lines no longer provide a guaranteed profit to the communication industry and are not growth drivers. Similarly, the time of change within Pharma is here, is now, and the clock will not be able to be turned back.

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30. Anonymous on August 19, 2010 2:17 PM writes...

#28 Agreed, use it with caution and examine the statistics from the model. Have the requisite number of training compounds etc.

It's always a good idea try and find trends between chemical descriptors and activity either with a 2D approach or 3D. The approach will always win out over 'shot-gun' med chem (I've used it with success).

The same people that talk-down qsar often use it without even knowing it. For example, if you've ever noticed a trend with increased lipophilicity of a functional group and increased activity and you made the next 'greasier' substituted compound, you've utilized qsar (2D).

If you can't see that qsar is a smart approach than you are the one that needs the 'strong medication'.

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31. g on August 19, 2010 2:20 PM writes...

Health care is taking up way too much of the economic pie and the population is just getting older. Drugs can be enormously costly and come with possibly terrible side-effects. Since life expectancy is 80+ years already, my guess is that advances in health care will not come from a drug but from lifestyle modifications and better care. We simply can't afford to throw money at drugs that only marginally extend life expectancy or improve certain symptoms of a disease while cause its own side-effects. The golden age of looking for pharmacological solutions to medical problems is over.

So many of these new biologics for cancer will extend life only one month! Palliative care can extend the life expectancy of terminal cancer patients by 3 months(www.nytimes.com/2010/08/19/health/19care.html?ref=health). If that were a drug, and with a side-effect profile like palliative care (lol), it would get approved with those numbers. Even fibromyalgia can be treated with tai chi (see New England Journal of Medicine http://www.nejm.org/doi/full/10.1056/NEJMoa0912611). We have reached a tipping point for pharmacological interventions for diseases. There are still diseases which can and need to be treated pharmacologically, but there are a lot of drugs that work good enough (for most) for many diseases.

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32. Hap on August 19, 2010 2:25 PM writes...

If there's an alternative to med chem, I'd like to see it. Or, rather, a working alternative. It seems like there are lots of alternatives to med chem for drug development, but no one's actually figured out how to make them work or whether they even could work at developing drugs. If there something in the role of car to displace the horse known as med chem, someone in pharma would be making drugs and lots of money, but there isn't.

Instead, there are bunches of people hoping that someone in India or China or at a small company will find the key to drug discovery and not realize its value, so that they can justify the destruction of their own (less successful) discovery technologies and cash out the value their predecessors generated. That's not displacement of med chem by superior technology or better approaches, but wishful thinking and greed alloyed with a lack of patience and a lack of concern with long-term consequences. Maybe if you can cure that, you can make some money in drugs.

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33. Skeptic on August 19, 2010 2:28 PM writes...

a. Funding agencies want quicker results at lower costs. Long term labor intensive investigations need not apply.

b. As a result of (a), Med Chems are being replaced by brute force techniques. Its no longer tenable to attempt to understand what is going on in biochemical systems, but instead to probe what they are capable of.

Therefore the trend is more sophisticated automated screening systems. Interdisciplinary skills are required, and while the huge body of organic chemistry knowledge is essential, it is no longer sufficient to be commercially relevant.

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34. Anonymous on August 19, 2010 2:35 PM writes...

#31

And this demonstrates just how moribund the current R&D model is. The failure is summed up by the fact that decades old chemotherapeutics are still the mainstay of treatment for most metastatic cancers; despite incredibly marginal efficacy.

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35. Cynthia on August 19, 2010 2:58 PM writes...

I agree with you that understanding the science is key. Unfortunately, the paradigm is not understanding but quick fixes, chasing surrogate markers that may or may not have anything to do with disease, and maximizing short term profits for VCs and startups as well as big pharma. Lifestyle will indeed be key to improving health, as many discover when they cut refined carbs, sugars and vegetable oils from their diets. Diseases will still exist and need cures though, but because we are studying the human organism in its unnatural state (bloated with metabolic syndrome or its precursor), we have no clue how to actually fix disease, but only how to change lab numbers. Also, ideology trumps objectivity and logic, and researchers see only what they want to see and look only under the streetlight for answers. Hence the failures in Alzheimers, diabetes and CVD. The public and investors are no doubt losing hope and interest, due to shoddy science which eventually is proved wrong, but only after billions have been invested.

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36. AlchemX on August 19, 2010 3:01 PM writes...

Derek is not god. Get over it people. It's just an opinion, a (slightly)positive view amongst all the negative.

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37. Wavefunction on August 19, 2010 3:25 PM writes...

I think industry is taking a big risk by suddenly focusing on biologics. Where's the proof of principle that biologics can replace many, let alone most, of our small molecule drugs? And where's the proof that biologics will become cheap enough to be mass produced for the majority of the world's population? Derek, I think you need to address these issues in a post. Industry is treading on a dangerous, untested path to its own peril.

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38. cynical1 on August 19, 2010 4:28 PM writes...

"Technological progress has merely provided us with more efficient means for going backwards."

Aldous Huxley

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39. barry on August 19, 2010 4:54 PM writes...

re #12:

It takes a bit of impetus to plunk down the dollars to launch a clinical study. Sometimes an impending quarterly deadline will shake that money free. My qualm is that a manager who has nothing worthy will put his/her best compound into the clinic while the head of another therapeutic area may have a backlog of half a dozen compounds all of which have met the criteria (ADME, validated target, tox, whatever). To advance one cmpd from each therapeutic area in such a scenario may look equitable from the boardroom, but it's cutting the chance of success in the Clinic in half.

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40. pete on August 19, 2010 6:21 PM writes...

"..but the number of veils is finite."

In that very sense (finite number) I continue to be an optimist about drug discovery -- and that even includes the difficult realm of cancer biology. That is, I'd agree anti-angiogenic approaches to combating solid tumors have had a bumpy ride in the clinic, but the story ain't over! And what about new approaches exploiting metabolic differences between cancerous versus non-cancerous cells ? Seems very plausible to me that this could yield part of a solid one-two punch combo-therapy some day.

But the big problem I see now is the effect of the poor employment landscape on a generation of budding US bioscientists. So where it's fine to take a more upbeat long-view of the current job situation as being a part of "growing pains", I can't help but think that the "bottleneck effect" on the number of bioscience graduates in the next several years will do a major number on US leadership in pharma/biotech. Last week's gloomy thread about the sad state of pharma chemistry jobs showed that a lot of science majors already are having serious second thoughts about la vie scientifique.

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41. LNT on August 19, 2010 6:35 PM writes...

I think most of the posters above (and even Derek) are missing the main point driving the changes we see today: Health care economics. A few of the posters alluded to it above: I think we are rapidly reaching a point in our society where we are unwilling to spend a bigger slice of our GDP in order to marginally enhance healthcare. We have healthcare technology that is very functional - most people that live a healthy lifestyle can expect to live to 80 or even 90. How much more do we really want? Are we willing to squander our entire GDP in our vain attempts to achieve immortality? No, I think that the population is largely satisfied with the status of our healthcare. Additional money needs to be spent in order to equalize access to healthcare, not to extend the lives of our parents and grandparents by another few months.

There will always be research into new treatments, but the privately funded research of the past is rapidly dying. We are approaching an age where drug research will largely be done in the government and nonprofit sector -- not because they are more efficient or knowledgeable -- but simply because economics won't allow us to continue down our present path. I've had a great ride for the past 10 years in the pharma industry. I'm going to keep hanging on as long as I can, but I certainly don't have any expectations of spending my entire career in this business.

The sad thing (for the sake of society) is that as all this restructuring is taking place, there are huge bodies of knowledge and expertise that are simply vanishing as people transition to other career paths. The "future generation" of drug-hunters (within the public sector) are going to have to reinvent the wheel in many cases as they “rediscover” many of the things found by big pharma years ago.

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42. Ross on August 19, 2010 6:44 PM writes...

#40

People seem unable to grasp that pretty much anything relating to cell signalling that may mediate the actions of a healthy cell will do very little to nothing in a cancerous cell, whose genomic instability has long since mutated it past the point of interdiction. The most promising research happening in oncology right now is being funded by the LEF. To quote from their site...

"Immunotherapy is one of the hottest fields in cancer treatment research. A potentially revolutionary cancer therapy was developed over a 10-year period by researcher Dr. Zheng Cui of the Wake Forest University School of Medicine. This approach, which has been highly effective in laboratory animals, is called leukocyte infusion therapy. Dr. Cui found that a subpopulation of white blood cells (granulocytes) is primarily responsible for killing cancer cells. He cured animals with different types of cancer by collecting concentrated numbers of granulocytes from healthy animals and infusing them into animals with cancer. Dr. Cui may have found a generalized principle by which the body’s immune system destroys cancer cells, which can be adapted for use in cancer therapeutics.

The Life Extension Foundation provided initial funding for a phase I/II clinical trial designed to test this new approach (leukocyte infusion therapy) to treating cancer in human cancer patients. Work is progressing on the clinical trial at the South Florida Bone Marrow/Stem Cell Transplant Institute in Boynton Beach, Florida under the direction of Dr. Dipnarine Maharaj."

There is a huge amount of literature on this approach in medical journals. It seems that cancer resistance various amongst the population quite dramatically, and there is a group of maybe 10% of the populous whose immune systems are extraordinarily effective at destroying cancerous cells. As this approach yields neither a patentable end product nor the likelihood of usage patent that could be upheld, the pharmaceutical industry has ignored he research and continues reformulating patent expired chemotherapeutics to milk some more revenue out of very old drugs.

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43. provocateur on August 19, 2010 6:47 PM writes...

at long last..
a sane post!
#41 is right!will you pay for the drugs you manufacture is the qZ?Answer the question honestly and you will understand the root cause of the problem.
third world diseases is one area i will bet the research will increase as their buying power increases ...not on other oncology drug which increases your overall average survival by 1 month.

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44. Marty on August 19, 2010 6:47 PM writes...

We'll as you said Derek - this week should hopefully be less depressing lets hope for some good news tomorrow ;-)

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45. Anonymous on August 19, 2010 6:57 PM writes...

#44

For end users (patients) there hasn't been any good news from the pharmaceutical industry for at least a decade, with the possible exception of some trivial lifestyle drugs. Countless billions of dollars spent, a lot of which has come from central governments, and it's been miserable failure after miserable failure.

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46. Cellbio on August 19, 2010 7:03 PM writes...

Partial agonist mentions the potential that the pendulum will swing back from biologics to SM. Was amused yesterday reading a newco perspective that pitched SMs beacuse of the "severe side effects of biologics". Other arguments, like cost of manufacture are made as well. A great Sm is still preferable, and yes the promise of clean and easy clinical study with biologics can now be evaluated with plenty of data.

Derek, not sure I agree with your final assessment, at least an interpretation of it. Knowing a bit more about a target or pathway or mechanism has not helped the overall success rate over the last few decades. I was trained in the molecular biology era, but now believe our future success lies in empirical approaches, combining chemistry and complex biology, not by gaining confidence or additional insight into GPCR or NHR mechanisms. Find the drug that impacts biology first, rather than screen for compounds that hit a target and then assess biological impact. Actually both strategies are OK, but the industry is almost fully on the target side, and I would say it should be weighted to the biology screening side. Kind of old-fashioned, from the time when success rates were higher.

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47. Marty on August 19, 2010 7:05 PM writes...

@45 yeah - wonder how pharma holds up when you compare with inovation in recreational drugs over the last two decades............

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48. Ross on August 19, 2010 7:18 PM writes...

#47
The pharmaceutical industry has never really liked having competition, so no surprise to find that the most vociferous lobbyists campaigning against any relaxation of cannabis legislation get significant funding from the pharma industry.Cannabis ameliorates the suffering of MS sufferers like nothing else available, but it seems personal freedom must never get in the way of profit.

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49. Morten G on August 19, 2010 7:23 PM writes...

Urgh. Drug discovery sucks - even if you prevent people from dying from one disease they just turn around and die from some other disease. Assholes. Or they get dementia and then die. Which is like dying before you hit the ground.

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50. expharma on August 19, 2010 7:46 PM writes...

HTS, combi, in silico, fragments and offshoring we can now make potent insoluble rocks that should cure (fill in the blank) if only more resources can be added

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51. Anonymous BMS Researcher on August 19, 2010 8:13 PM writes...

"You are in a maze of twisty little passages^H^H^H^H^H^H^H^H signaling pathways, all alike"

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52. Rod Tidwell on August 19, 2010 8:16 PM writes...

Blah...Blah....Blah

Wall street says:
"Show Me the Money"

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53. Jumbo on August 19, 2010 8:29 PM writes...

A lot has already been discussed so I'll just make a few points.

1) There is still a serious need for chemists globally, but not where you can live in a McMansion and have an Olive Garden within walking distance. How many NA and EU medchemists have considered moving their families to China, India, even the Ukraine? There are outfits that have various elements of drug discovery (primate models, structural biology, computational power) but lack the medchem expertise. But no one from Groton (or Ann Arbor, or Indianapolis, or Leverkusen) wants to move to Mumbai or Shanghai or wherever the current need for medchemists is. Its a legitimate choice, I'm not criticizing it, just making a small point.

2) It's already been pointed out but just as genomics hasn't been able to solve the target dilemma, so too combichem, HTS, etc was a failed model on the chemistry side. Viz the poster pointing out the McKnight paper: Gee - injecting compounds into animals to see what happens. How 1950's!

3) I agree that the healthcare debate is putting pressure on drug costs, but it is worth reminding everyone that most healthcare analysis puts the costs of drugs as contributing no more than 33% of the overall increase in health costs. Nevertheless, the pendulum is swinging to generics and will stay there a while. We aren't going to see the '80s or '90s in terms of drug launches for a while. That will vanish a lot of big companies as old school pharmas (i.e. they will look more like generics) and the industry will shrink. But some stubborn people will keep at it, and someone will solve one of the 'unsolvables' (AD?? One of the solid tumor cancers? T1D?) and all of a sudden pharmaceuticals will become sexy again. I probably won't be working any more, being north of 50, but my son still, against all odds, may become the next generation of drug hunter. It's still a great calling and I would not dissuade him from pursuing it, ever.

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54. Ross on August 19, 2010 9:04 PM writes...

#53

It's a particularly unjustifiable 33% given what an absolute racket pharmaceutical procurement is. You could replace 50% of drugs in use in the clinical environment across the board with tic-tacs, and not impact patient care to any significant degree. That's an awful lot of spending for extraordinary little clinical benefit. Still, I guess the industry has to pay its army of salesmen to bribe clinicians to prescribe its latest side effect ridden snake oil.

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55. Rich Rostrom on August 20, 2010 12:45 AM writes...

The immediate future for med chemistry and drug development is in drugs for infectious diseases. There are a bunch that have never been properly tackled because they mostly attack poor Third Worlders. Schistosomiasis, for instance.

Others have stayed "below the radar" because the harm they do is low-level and unobvious. There is increasing evidence that toxoplasmosis causes or contributes to serious conditions such as schizophrenia. But nobody knows how, and there are billions of toxo carriers with no detectable problems.

There will also be a need for new drugs to fight IDs that have become immune to older drugs. Various Cassandras have been saying for years that bacterial infection could become as untreatable as it was a century ago. If we need to invent a whole new arsenal of anti-bacterials, there will be a lot of med-chem work to do.

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56. Karlos on August 20, 2010 1:00 AM writes...

no. 54

Actually tic-tacs would probably have a significant benefit given that adverse reactions to drugs account for a significant percentage of hospitalizations. (With some assumptions - I'm not sure similar studies have been conducted with tic-tacs!)

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57. likeitis on August 20, 2010 1:07 AM writes...

Immediate solution to the healthcare economic crisis:
*Put to sleep* all people over the age of 70/75/80
(select your exit point and strategy)

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58. Jose on August 20, 2010 1:32 AM writes...

Re: 55. Rich Rostrom... the solutions to tropical diseases, almost without exception, have nothing whatsoever to do with pharmaceuticals. The US did a great job of clearing malaria from the SE in the 1930's and '40s via water improvements, sanitation and vector control. Quinine and chloroquine played a very minor role!

RE: antimicrobials, it's a catch-22. Any new modes of action, active against "problem" bugs, are placed on a highly controlled schedule, which makes market share (and profits) minuscule.

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59. LAM on August 20, 2010 9:15 AM writes...

# 55
The need for new antibacterials has been talked about for the past 20 years. Yet, despite much effort, with application of genomics looking for any new target, there have been no new breakthroughs in new classes of compounds to treat areas of highest and possibly emerging needs, including resistence. And this is part of the bigger conundrum: just because someone says there a need and a justification does not mean there is a way to get there at any cost.

Yet, we have to recognize the progress made in other areas related to infection with antivirals, vaccines, etc.

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60. anon on August 20, 2010 10:05 AM writes...

at the end of last century the spiel was that targeted therapy would be the paradigm- specific compounds for select groups- unfortunaely marketing wants the one compound many indications. Remember the adds for Valium- mother's little helper? The psychotropics are back- LSD and Ketamine the Chemists' helper.

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61. john on August 20, 2010 10:24 AM writes...

Astronomy teaches us that greater knowledge does not directly translate into a proportionally greater ability to influence outcomes.

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62. CMCguy on August 20, 2010 3:42 PM writes...

#46 Cellbio I do mostly agree that doing more of "old-fashioned" approach still has viable utility for drug discovery however I would think all the "hype" and other "paradigm shifts" that has occurred in past few decades makes this impossible to be even considered in a project. Most Management/VCs would not support simply as not proper Image wish to portray and even on the technical side many in the lab have gotten catch up in the whiz-bangs not sure would know really how any longer. I am out of direct touch with this process currently but I suspect old fashioned mechanism involved/forced greater intradisciplinary interactions and communications (even if in friendly rivalry) whereas as in today's environments appears don't know how to feed off each others expertize to achieve progress.

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63. InfMP on August 20, 2010 5:43 PM writes...

I think I've been waiting a few years for this post.

Now I'm ready to keep trying

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64. Cellbio on August 20, 2010 9:38 PM writes...

CMCguy,

My experience doing this, even with VP support at one level, is that indeed the organization that is aligned to meet their metrics in the accepted paradigm will not support the approach. In part it was due to a belief that knowledge of a target (one of the targets?) meant we could rationally design clinical trials and limit or understand toxicity through carefully designed dosing to achieve desired exposure, and this would be compromised with biology first approaches. While pleasing on the surface, I never knew what measure of exposure we were aiming for, Cmax, Cmin, AUC, and dosing schemes in early trials did not seem to reflect targeting dosing, unless the math curiously always settled on the same mg/kg numbers (0.1, 0.3, 1.0....). For this an other objections, I could offer rational rebuttals that did appear to be accepted intellectually, but nonetheless the project was rejected. The final argument put forth against was..'What if we dose in Ph1 and see elevated liver enzymes, we won't know if it is target mediated or not'. However, I never saw a target based program solve the mechanism of toxicity, or prove that it is not mediated by the target. In essence, such a high standard was set for biology first projects that nothing could move forward despite the quality. Meanwhile, "hot" targets, like BASE and a few others, would crow about paper thin safety margins for monster molecules with horrible exposure and really complex metabolism. In my view, it seemed the promise of a target, based often on mouse KOs, trumped the ugly reality of the pharmacology of inhibition. But there you go, I was proposing to have pharmacology be the driving force in projects, and that just puts reality in the way of peoples plans, like the target champion building a career off of advancing their program, or the manager rewarded for molecule portal advancement.

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65. Anonymous on August 21, 2010 12:56 AM writes...

#57

Hey why stop with people over 70, we could save lots and lots of health dollars by putting "to sleep" the mentally ill and disabled, plus all the sickly and physically disabled young people and children, too. I think there is already a 1930s German road map for this approach available for you to impliment.

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66. anaonymous on August 21, 2010 11:02 AM writes...

@ 55/58

Don't forget DDT, which is the most formidable weapon we have against malaria.

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67. likeitis on August 22, 2010 11:12 PM writes...

#65
The legions of seniors are the primary healthcare economic headache, as China will realize in about 20? (guessing here) years time.
Many people would probably consider *controlled checkout* to be less draconian than controlled fertility.
The newborn have at least positive future economic contributory potential (unlike the aged).
Those with inherited wealth are uniquely (and comfortably) positioned to set an example. The poor often can't wait to end their misery. The main problem is the hopelessly overmortgaged mid-life redundant cast-offs, whose rapid health decline has been all but assured by the financial catastrophe. Perhaps we should *forgive* their debt, just as we seem to have done for the *blameless* filthy rich bankers?
Justice and Payback in our time!

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68. Anonymous on August 22, 2010 11:28 PM writes...

#67

Yeah, and the ....bankers caused the 1920's problems for the Germans too. We all know how that problem was solved. 56 million dead people in Europe and another 17 million dead in Asia was where your thinking took the world.

But hey maybe you can dawn a brown shirt and some jack boots to march us all to the promised land. Now get to work on the camps and ovens.

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69. likeitis on August 23, 2010 12:23 AM writes...

#68
Those with vision are doomed to foresee solutions that are too radical to be ethical.....and to be insulted by jealous sleazeballs.
BTW, I do not claim credit for these ideas.... Huxley (Brave New World) foretold our future as unthinking controlled drones on The Kool Aid (AKA: Soma) a long time ago...and also what happens to those intelligent enough to see through the smoke....so I will stop here!!QQ!!

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70. Jonadab the Unsightly One on August 23, 2010 5:08 PM writes...

> We keep pulling back veils, but
> the number of veils is finite.

Uh-huh, sure. For any given thing you're trying to figure out (leukemia, say), the number of veils may be finite. I wouldn't care to try to prove that, but I'll accept it as a working postulate for the moment.

I'd bet the farm on the number of veils overall being infinite, though, because I'm pretty sure the cardinality of the set of all puzzles we might at some point try to figure out has got to be at least aleph-sub-one (cardinality of the reals), if not higher. (I can readily imagine that it might even be aleph-sub-two.) Multiply that by a finite number of veils for each of them, and your total number will clearly be infinite.

There will always be more stuff to learn. You can take that to the bank.

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