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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: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

« A Note to Andy Grove | Main | Fish Nor Fowl »

October 26, 2011

Francis Collins Speaks

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Posted by Derek

With all the recent talk about the NIH's translational research efforts, and the controversy about their drug screening efforts, this seems like a good time to note this interview with Francis Collins over at BioCentury TV. (It's currently the lead video, but you'll be able to find it in their "Show Guide" afterwards as well).

Collins says that they're not trying to compete with the private sector, but taking a look at the drug development process "the way an engineer would", which takes me back to this morning's post re: Andy Grove. One thing he emphasizes is that he believes that the failure rate is too high because the wrong targets are being picked, and that target validation would be a good thing to improve.

He's also beating the drum for new targets to come out of more sequencing of human genomes, but that's something I'll reserve judgment on. The second clip has some discussion of the DARPA-backed toxicology chip and some questions on repurposing existing drugs. The third clip talks about the FDA's role in all this, and tries to clarify what NIH's role would be in outlicensing any discoveries. (Collins also admits along the way that the whole NCATS proposal has needed some clarifying as well, and doesn't sound happy with some of the press coverage).

Part 5 (part 4 is just a short wrap-up) discusses the current funding environment, and then moves into ethics and conflicts of interest - other people's conflicts, I should note. Worth a lunchtime look!

Comments (16) + TrackBacks (0) | Category: Academia (vs. Industry) | Drug Assays | Drug Development


COMMENTS

1. anon on October 26, 2011 12:07 PM writes...

"wrong targets are being picked"

...because the light's better over here!" Da-dum-psssht.

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2. azetidine on October 26, 2011 12:14 PM writes...

"the failure rate is too high because the wrong targets are being picked"

This is EXACTLY right. The only determinant of success in drug discovery today is the choice of the target. Our medicinal chemistry skill set is completely adequate to the task of attacking a validated target.

There needs to be a change in paradigm if there's going to be any future success in drug discovery. Analoging for 3-5 years on some literature target that "looks good" will rarely lead to a drug any more, mainly because the vast majority of the biology out there is actually wrong (see the recent Atlantic article http://www.theatlantic.com/magazine/archive/2010/11/lies-damned-lies-and-medical-science/8269/). Doesn't matter how good of a chemist you are, if the train is pointed toward the cliff you are going over with it.

How about this approach: Spend 3-5 years just validating targets. If you happen to be lucky enough to find one, then the drug discovery effort is essentially assured of success. In either case, you are burning money for 3-5 years, but if you don't have a truly validated target, it's going to be a waste.

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3. bbooooooya on October 26, 2011 1:13 PM writes...

"There needs to be a change in paradigm"

A change in paradigm, yes! That will solve everything! Especially if we can synergize the genetic/proteomic biologic underpinnings of disease by application to translational medicine using a multi-faceted, inclusionary, approach.

YES WE CAN!

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4. CR on October 26, 2011 4:05 PM writes...

Once this post was put up, it was only a matter of time until the Pharma folks ripped Dr. Collins. I'm not with the NIH and am a former Pharma medicinal chemist - so no skin in the game. But nobody can disagree with the fact that Pharma is not producing anymore (especially wrt neuroscience). This can be from a number of issues - poor management (those damn MBA's - we chemists know so much more about running a company), the FDA (we chemists know so much more about drug approvals), low hanging fruit already picked (we chemists know so much more about getting drugs to the market - oh wait, those chemists 20 years ago knew so much more), etc. Yet anytime someone else brings a different way of thinking about things, it is always shot down on this blog by the comments. It is a shame that everyone on these boards are such awesome chemists/businessmen/regulators and it's everyone else that is keeping them from bringing drug after drug to market. But the one common theme is this: excuses.

Face facts, Pharma is not coming back anytime soon. Can the NIH do it better/the same/worse? At least they are still "trying" to do some form of drug discovery. All the Pharma industry is doing anymore is "pretending" to do drug discovery while slowly shifting all the jobs somewhere else. And if you want a job in this fascinating area of research, better jump on board and hope the NIH works out, because otherwise, there is no future.

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5. MolecularGeek on October 26, 2011 4:52 PM writes...

CR: RIght on. They may not do it in a way that everyone agrees with, but the NIH IS putting money into trying to do early stage drug development, and paying for jobs for some of the industry refugees who would otherwise have to consider leaving science altogether or taking intensive mandarin courses. Do we really want to have all our technical knowledge migrate overseas within 50 years?

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6. old timer in pharma on October 26, 2011 7:44 PM writes...

This shows how little Collins understands about what has been tried in Pharma on "gene to dream (drug)", how little he appreciates about what it takes to identify legitimate new drug candidates, and to then progress compounts through safety, ADME, clinical trials to successful approval. And, after all that, be able to manufacture, sell, get prescribing uptake, in order to recapture the investment costs...just to get out of a financial hole and break even. Most new drugs do not become "billion dollar molecules". A true idealized academic view point. Of course, lighting sometims does strike.....with Lyrica as a case-study in point.

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7. Silvernut on October 27, 2011 1:33 AM writes...

I believe they should shut them all down and be done with them.
They clearly don't have a clue what they are doing or what is needed vs what is the most profitable.
Good God--reminds me of 80's stupid all over again.
Head to China boys everyone else is.
We can buy everything we need from there a lot cheaper..

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8. LeeH on October 27, 2011 7:56 AM writes...

It's amazing that people still think that the problem with finding drugs can be attributed to a single factor. This is an example of Ed Tufte's comment that "Powerpoint makes you stupid" - the reduction of a nuanced problem down to bullets that will fit on a single slide (note that I don't completely agree with the saying, but this issue supports his thinking).

Target selection is the most obvious reason for a drug failing - it's the first step in the process, and often only manifests in phase II or III - but ignoring all the other factors reveals a lack of familiarity with the process.

On the other hand, I do feel that target selection is a great area for public research. It's highly speculative, and the cost should be spread out as widely as possible. How to do it reliably (if it's even possible), in the end, is the real problem.

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9. Cellbio on October 27, 2011 8:40 AM writes...

Or, isn't the problem, or more correctly stated, a large contributing factor, the fact that we "pick" targets? Until we compliment molecular target driven drug discovery and lead optimization with biologically driven screening and SAR building we will be limited by two factors: the ability to truly validate a target in a way that better predicts clinical success, and the clinical utility of hitting any single molecular target. After all, our real target is perturbing biology, so why not start there? Not that molecular targets have no value in drug discovery, but no one can look at the past 15-20 years and make a solid argument that target picking is the one and only way to go for success.

And, hasn't the role, if you will, of academic research in drug discovery been exactly the elucidation of biochemical and biological roles of proteins? Isn't this how the lion's share of validation has been done? After the typical type of work currently done for "validation" (KOs, expression profiling, genetics, etc), is there really anything more that will move the needle much, other than exploratory clinical trials? I wish I knew what it was, because that would be the basis of the next great company.

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10. azetidine on October 27, 2011 9:33 AM writes...

#9:

It is precisely my point that the so-called "validation" done in academic labs is complete crap for the purposes of deciding on the target. The data is out there now; it is essentially impossible to duplicate the vast majority of these academic results. It might be a place to start, but I wouldn't begin a target-based drug discovery project today without a complete (and I mean complete) set of original target validation experiments.

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11. molecular architect on October 27, 2011 10:14 AM writes...

To reinforce LeeH's comment (#8), the only way to truly validate a target is to treat patients with a molecule that hits that target and determine the clinical response. Thus, it's a circular argument: you need a validated target to develop a drug and you need drugs to validate the target. This is not a simple problem that can be broken into discrete steps. The Medicinal chemistry and the target validation are intimately intertwined. Since most of the non-Pharma/Biotech folks doing target discovery/validation do not have their own medicinal chemistry labs, the effort by NIH to make validated probes available to the research community is extremely valuable. It may have been overhyped and not delivered all that was promised, but this is a logical role for the public sector in the drug discovery process.

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12. RespiSci on October 27, 2011 10:37 AM writes...

I suggest to approach the videos as a drinking game. Down a shot everytime Dr. Collins says 'bottleneck", "new technologies","new ideas" and "opportunity" oh and don't forget the word "critical". Winner is the one left standing by the 4th video.

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13. Cellbio on October 27, 2011 11:57 AM writes...

Molecular Architect,

I don't disagree with your statement, generally I think the same, but would add that a single compound in a clinical setting can only give you outcomes consistent with the hypothesis of the role of the target, but not really validate the target. At that point, the data really only validate the molecule, as additional unrealized pharmacology (or pharmacology known and not part of the nice story) account for biological impacts that have a meaningful role in the clinical outcome.

I think Gleevac and anti-CD20 antibodies are examples, probably statins. Anti-CD20 is interesting to me, as people thought that making fully human antibodies would improve upon the chimera, not so. perhaps the chimeric molecule has a really nice profile of binding to the antigen while also eliciting an optimal amount of immunogenicity for ADCC. Hard to design, but the sort of thing that can come through biological screening that is paired with clinical exposure for validation of molecules. Yes the target matters, but the molecule is the drug. BTW, the "architects" of the molecules are my favorite people to work with, and they need more clinical data to bring back to the drafting table.

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14. Molecular architect on October 27, 2011 12:54 PM writes...

Cellbio,
You're absolutely correct, the whole system of drug:target:PK:PD:metabolism:whole_organism is extremely complex. One cannot "validate" a target without the proper tools. Those tools are drugs and human patients. Many molecules that hit their targets with exquisite selectivity and potency fail to become drugs even when the target's role in disease is clearly understood. It isn't easy and one of the hardest parts of the process is getting the clinical data back to the people designing the molecules and bioassays.

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15. Curious Wavefunction on October 27, 2011 4:13 PM writes...

Target validation cannot come from just medicinal chemistry. Gene knockouts, antibodies and a variety of techniques need to reach the same conclusions about a target before it can possibly be considered "validated". And as someone mentioned, true validation can't really come unless the compound's in the clinic. How many "validated" targets have failed in large-scale trials because of lack of efficacy?

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16. Bio(chemist) on October 28, 2011 5:11 AM writes...

@2
"How about this approach: Spend 3-5 years just validating targets. If you happen to be lucky enough to find one, then the drug discovery effort is essentially assured of success. In either case, you are burning money for 3-5 years, but if you don't have a truly validated target, it's going to be a waste."

What a crock of pompous crap!!!! Please regale me with the endless stories of Med Chem effort --> successful drugs in targeting phosphatases, protein-protein interactions, selective nuclear hormone receptor modulators, selective transcriptional modulators, etc., etc.. How terriby naive you are!!

PS - lots of "good targets" in the above bins. Now go to it!

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