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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

« Gegen die Dummheit . . .Well, Guess Who Wins, Again | Main | GSK's Response to the Sirtuin Critics »

August 25, 2010

Where Are the Cures?

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Posted by Derek

Emily Yoffe at Slate has a very accurate piece up on just how hard it is to make progress against things like Alzheimer's, Parkinson's, and other neurodegenerative diseases. The contrast with the hopes of patients - and the hype often surrounding the initial discoveries - is painful.

And we're back to that optimism/realism tightrope. On the one hand, I don't see any reason why we shouldn't be able - eventually - to stop such conditions in their tracks, or to keep them from starting in the first place. (Reversing the damage once it's done, though, is much more of a stretch, to me). But on the other hand - sheesh, we really, really have a lot to learn about these things. The likelihood of any one discovery being the key breakthrough is small - nonzero, but small. So in the long term, I'm an optimist, but in the short term, well. . .every little bit helps, and most of the bits are going to be little.

That's not the sort of news you want to give to someone suffering from these conditions, of course. That desire for encouraging news, along with plenty of other good intentions (and a few not-so-good-ones) leads to the cycles of hype that we've seen over and over. Stem cell research is a perfect example. There really are huge possibilities there, extraordinary ones. But our level of ignorance is also extraordinary. And to go out and make claims that we're going to be able to cure X and reverse Y soon, based on our present knowledge, is just plain irresponsible.

But plenty of people do just that - politicians, headline writers, and others. And then people who only know what they see in the news wonder where things went wrong, and how come these wonderful cures haven't arrived yet. It all makes explaining the real situation that much harder.

It's not like the real situation is even all that terrible. As I said above, I really do think that these diseases - and many others - are eventually going to be treatable. No one likes that word "eventually", though.

Comments (21) + TrackBacks (0) | Category: Press Coverage | The Central Nervous System


COMMENTS

1. cancer_man on August 25, 2010 9:40 AM writes...

My memory isn't so great, but didn't public figures like Oprah Winfrey and Clinton's Health and Human Services Sec claim that HIV/AIDS would wipe out a large part of America by 2000?

Inhibitors started working well in 1995, but was this a surprise or did researchers have a pretty good idea good treatments were coming back in 1992 and 1993?

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2. qetzal on August 25, 2010 9:41 AM writes...

Typo in paragraph 2, sentence 2: "shouldn't" instead of "should"?

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3. rhodium on August 25, 2010 10:05 AM writes...

Is there a theoretical reason to believe that a small, drug-like molecule exists that can treat each known disease? Not reverse damage, just stop it. Even if you add larger molecules like antibodies with enhanced specificity or binding site size are you sure there is something that can work? The second law of thermodynamics or the Arrow impossibility theorem limit some outcomes, is there an analogy in the coupled reaction network that is biology?

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4. milkshake on August 25, 2010 12:35 PM writes...

Drugs often work all the time for the reason not initially anticipated and drug candidates fail all the time for unforeseen reasons. Biology is more complicated and target-driven rational drug design aided by crystallography may not get you far enough in hard projects.

I would like to see much more whole cell / animal-based assays, assays that are looking at outcome in a semi-realistic disease model rather than going after a specific target (that is supposed to work in a way you think you understand, of which you ourified the binding domain, use elaborate chromophoric substrate, one which you overexpressed in cells and added a reporter system that makes it glow, etc).

It is always possible to find the target once you identify that your compounds do something remarkable in live cells. And all your hits are cell-permeable to begin with.

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5. D on August 25, 2010 1:03 PM writes...

Couldn't agree more with #4!!

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6. DV Henkel-Wallace on August 25, 2010 1:20 PM writes...

cancer_man's comment suggests an interesting point: people remember that HIV/AIDS came "out of nowhere" into the public conciseness and then was pretty rapidly rendered treatable. Which has perhaps misset peoples' expectations...?

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7. barry on August 25, 2010 1:25 PM writes...

re: rhodium (#3)
With scant exceptions, small-molecule therapeutics work by blocking a receptor, an ion channel or an enzyme. That's great if your pathology is due to an excess of signalling or an excess of enzymatic activity ("Gain-Of-Function"). Not so good if the problem is Loss-Of-Function. There are exceptions (e.g. we can administer B12 i.m. where the "intrinsic factor" is lacking)but they're scarce.
If you show that CML is caused by signalling through an abnormal protein kinase, we can block the disease by blocking BcrAbl. If you show that lots of human cancer seem to be driven by broken p53, we don't have a good small-molecule strategy to repair that.

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8. CMCguy on August 25, 2010 2:32 PM writes...

Yoffe's piece mentions sometimes the scientists themselves make claims that may overreach in order to attract funding, I do agree with Derek there seems to be much irresponsible exaggeration of potential promise and/or time frames required, particularly from politicians and journalistic side. I can attribute the former mostly to enthusiasm toward research goals however with the later groups is more to feed off an largely uninformed public for there own gains. Along those lines I would say about every other week the local paper has an article with headlines suggesting "cures" for something, often coming out of local Universities, only to read further and find a story of some lab research that will start testing in animals in another year or two, at which point shake my head.

The whole system for drug development may be inherently dependent more on hype rather that realism as at all stages from discovery to marketing progress appears controlled by unbalanced expectations, potential and pedigree. This can cause things to be pushed further than they should or not be recognized for true value. I would offer that "occasionally" eventually things do work out leading to a worthwhile drug.

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9. Ross on August 25, 2010 3:06 PM writes...

Derek Lowe, has worked in the industry for 20 years. Drugs that he has directly worked on in that time that have come to market, likely zero. When an industry can be so replete with failures as the pharmaceutical industry is, and yet still be obscenely profitable, something is wrong.

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10. retread on August 25, 2010 3:20 PM writes...

"just how hard it is to make progress against things like Alzheimer's, Parkinson's, and other neurodegenerative diseases"

Not so at all. 40 years ago next month (1) I got out of the Air Force (2) L-DOPA was released in the USA (3) I was charged with running the L-DOPA clinic -- because docs in the USA had no experience with it (4) I saw people get out of wheelchairs.

I'm going to do a post next month about what it was like back then.

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11. LAM on August 25, 2010 3:24 PM writes...

#4: Yes, biology is often unpredictable, often inconveniently gets in the way of clean, clear, simplified hypothesis and conceptual models. Chemists can often struggle when biology results turn out to be messy, not conforming to the proposal or latest compound design strategy. Somtimes, the reductionest approach to science is simply too simple.

Unfortunately, many human disease states have poor to no predictive preclinical tools. Types of cancers, Alzheimers require human clinical evaluation, not without large efforts to find better predictive methods. So until, or unless, there are some breakthroughs, we are all stuck within many of today's biological paradigms.

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12. retread on August 25, 2010 3:46 PM writes...

"just how hard it is to make progress against things like Alzheimer's, Parkinson's, and other neurodegenerative diseases."

Not so at all ! (1) Forty years ago next month L-DOPA was released for use in the USA (2) I got out of the Air Force (3) I was charged with running a newly set up L-DOPA clinic (4) I watched people get out of wheelchairs.

I'm going to do a post about what all this was like next month (and how the FDA caused needless suffering by refusing to accept the European studies, causing them to be repeated in the USA, prolonging the release of L-DOPA by several years).

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13. Tim D on August 25, 2010 4:17 PM writes...

"I'm going to do a post about what all this was like next month (and how the FDA caused needless suffering by refusing to accept the European studies, causing them to be repeated in the USA, prolonging the release of L-DOPA by several years)."

True enough, but don't forget about European/UK approval of thalidomide and the FDA reviewer who delayed entry for US approval...that case will remain as an inflection point in FDA annals.

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14. retread on August 25, 2010 5:03 PM writes...

#13. Tim D: Excellent point. However there were many drugs for sleep back then so delay didn't really harm the insomniac. Our drugs for Parkinsonism before L-DOPA and its heirs were truly lousy. Given a choice between Parkinsonism and insomnia, which would you choose?

More next month.

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15. ANON 1 on August 25, 2010 7:39 PM writes...

Following the theme, today's example of hope, or possibly hype:

http://www.msnbc.msn.com/id/38854884/ns/health-cancer/

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16. sgcox on August 26, 2010 11:24 AM writes...

PLX4032 is a solid drug candidate with a good rationale. It might actually do some good at the end. One worring part of that trial is that effect was only transient in most patients

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17. Ross on August 26, 2010 12:01 PM writes...

No, PLX4032 is almost worthless. There is no clinical evidence that the reduction in disease load brought about by this drug has any significant impact on survival. What it will do is give oncologists a tool whereby they can say to terminally ill patients...

'the treatment is going really well, your scans show we shrunk your tumours 50%. I suggest we keep you on this hugely expensive drug'

Of course, the patient will still die of their metastatic melanoma, but the disingenuous suggestion that a reduction in disease burden will increase survival, will ensure this becomes a very profitable drug. Given the pharmaceutical industry's failure to produce treatments that actually work, their efforts now seem focused on getting approval for compounds that are superficially ameliorative, but of no significant fundamental benefit to patients.

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18. srp on August 26, 2010 7:39 PM writes...

Maybe tools like the following will help unravel some of the puzzles one day:

http://www.sciencemag.org/cgi/content/abstract/329/5993/830

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19. rob j on August 28, 2010 6:14 PM writes...

RE:#13
L-dopa (sinemet) is either referred to as the gold standard in pd treatment or basically inadequate but it's the only drug that helps even if the help is short-lived.

Not very good for 40 yrs of biological advances....save the laudatory reports please.

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20. rob j on August 28, 2010 6:15 PM writes...

RE:#13
L-dopa (sinemet) is either referred to as the gold standard in pd treatment or basically inadequate but it's the only drug that helps even if the help is short-lived.

Not very good for 40 yrs of biological advances....save the laudatory reports please.

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21. Bryan Maloney on October 27, 2010 6:35 PM writes...

Regarding diseases like Alzheimer's, I can tell you where the cures are: They're right behind discovering the causes. Right now, we actually have very little evidence regarding what causes AD. Yes, APOEe4 has a strong dose-based risk association, but you can be e4/e4 and never get AD, just like you can be e2/e2 and get AD. Likewise, there is no association between e4 genotype and AD among some of the Yoruba. As for the beta amyloid hypothesis, I might be a bAptist, but I can't really point to all that much evidence that is more conclusive than that of the tauists or even the synners.

Part of the problem is that we still rely on end-point assays for our etiology studies. We measure AD+ vs. AD- populations and try to associate it with some other difference between the two that we find. However, such a study never answers whether or not the associated measurement led to AD or AD led to the associated measurement. Likewise, such an approach ignores the possibility of latent sequelae to earlier exposures/stress.

Just a few things I've noted over the years.

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