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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

« The Prospects of an Academic Job | Main | What Structures Have Turned on You? »

July 15, 2014

K. C. Nicolaou on Drug Discovery

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Posted by Derek

K. C. Nicolaou has an article in the latest Angewandte Chemie on the future of drug discovery, which may seem a bit surprising, considering that he's usually thought of as Mister Total Synthesis, rather than Mister Drug Development Project. But I can report that it's relentlessly sensible. Maybe too sensible. It's such a dose of the common wisdom that I don't think it's going to be of much use or interest to people who are actually doing drug discovery - you've already had all these thoughts yourself, and more than once.

But for someone catching up from outside the field, it's not a bad survey at all. It gets across how much we don't know, and how much work there is to be done. And one thing that writing this blog has taught me is that most people outside of drug discovery don't have an appreciation of either of those things. Nicolaou's article isn't aimed at a lay audience, of course, which makes it a little more problematic, since many of the people who can appreciate everything he's saying will already know what he's going to say. But it does round pretty much everything up into one place.

Comments (58) + TrackBacks (0) | Category: Drug Development | Drug Industry History


COMMENTS

1. Anonymous on July 15, 2014 7:46 AM writes...

yeah, i think i'll read it when its from someone who has put a compound into man. Be interesting to hear from academics who have done that: mike jung, others?

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2. newnickname on July 15, 2014 7:53 AM writes...

@1: Richard B Silverman: Lyrica (and work on many others). Derek discussed Silverman's discussion of it here:

pipeline.corante.com/archives/
2008/03/25/getting_to_lyrica.php

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3. Anon2 on July 15, 2014 9:11 AM writes...

@1 your inability to think of more than one academic who has "put a compound into man" speaks more to your own ignorance than the state of academic drug discovery. I have yet to work for a professor who hasn't achieved that, either through a compound synthesized in their own lab, or with a close chemical derivative to a molecule developed in their lab that was synthesized at a startup they founded.

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4. entropyGain on July 15, 2014 9:32 AM writes...

Sometimes a thing being said by one person rather than another, is heard by one group better than if the other person had given the same message.

In this case if the NIH and academic "translational" types get a better appreciation for what drug discovery is from KC, then this will be a good thing.

From sitting on NIH study sections, I can tell you that despite a few academics who "get it" (Mike Jung obviously being one of them) the vast majority of applications I've seen do not. My personal pet peeve is the RO1 proposal to take the 10 uM screening hit into four years of in vivo and mechanistic studies. Can't tell you how many times I've seen that one since the "Roadmap" effort...

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5. Lyle Langley on July 15, 2014 10:28 AM writes...

@1 Anonymous...

You do realize that the vast majority of scientists working in the Pharma/Biotech industry have not "put a compound into man", nor will they? Should we dismiss those ideas as well? Part of "putting a compound into man" is hard work, intelligence, and luck. The industry will never change if these "outsider" perspectives are dismissed out of hand.

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6. Anonymous on July 15, 2014 10:37 AM writes...

Perhaps what commenter #1 was trying to say is that it's somewhat unusual that an academic titan in the field of total synthesis is writing about something he has not directly been involved in.

Similary, it would be somewhat unusual if a 30 year veteran in medicinal chemistry wrote about the future of total synthesis. I wonder what kind of comments an article like that would garner...

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7. Anonymous on July 15, 2014 10:37 AM writes...

As an unemployed medicinal chemist with 30 years of experience, I find it rather ironic that some (insert appropriate noun of your liking) with tenure is trying to inspire students to enter a field where you can't make a living any longer but in doing so it brings a constant flow of cheap renewable labor into his lab. No, I don't think I'm going to pay to read his narrative of the wonders of drug discovery. I'm going to go apply for more jobs outside my field that pay really poorly which I will fail to get because they gave it to someone half my age with an H1B visa. Thank you very much, KC, but I'll take a pass.

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8. An Old Chemist on July 15, 2014 11:03 AM writes...

E.C. Taylor discovered Alimta. He was awarded the Alfred Burger Award for it. It is billion dollar drug.

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9. newnickname on July 15, 2014 12:04 PM writes...

@1: Craig Crews, Kyprolis. From Yale to Proteolix to Onyx to Amgen:

crewslab.yale.edu/ research/ carfilzomib-kyprolis

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10. Anonymous on July 15, 2014 12:08 PM writes...

jeff kelly, tafamidis

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11. petros on July 15, 2014 1:45 PM writes...

Malcolm Stevens temolozide

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12. anonymouse on July 15, 2014 1:49 PM writes...

some people are good at writing reviews and some people are good at discovering drugs. live and let live !! KC is an educator so let him do his thing. its always positive.

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13. bad wolf on July 15, 2014 2:22 PM writes...

Like most publications Derek links to, this is not "in the latest Angewandte" but rather an online pre-publication version.

Does anyone else just try to keep up with journals issue-by-issue, or is everyone just reading the ASAP and Early View articles? And do they think that's necessary, or a matter of keeping up with the Jones?

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14. B on July 15, 2014 2:35 PM writes...

that guy from Emory. Liotta.

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15. Lyle Langley on July 15, 2014 2:46 PM writes...

@13, bad wolf...

Are you upset? I think most of us (speaking in general terms here) have updates sent to us when there are new articles (ASAP, etc.) so we get them as they are available on-line. Since I (and probably many of the readers here) have not read an actual paper journal in a number of years, why wouldn't we take advantage of the early releases? It's neither necessary nor is it keeping up with the Jones'; it's simply how articles are accessed now. I don't discriminate between an "issue" or an "ASAP" article; once on-line they are one and the same.

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16. Anonymous on July 15, 2014 3:15 PM writes...

@13

I agree with Lyle and keep up with ASAP, Early View, etc. versions of research articles. I do not look at 'Just Accepted' versions, however, since the page formatting makes them hard to read.

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17. TX raven on July 15, 2014 3:26 PM writes...

I admit my first reaction was "why is KC talking about something he is not known for having experienced close by?"

However, while not previously unheard of, most of the 20 recommendations he gives are right on target, in my opinion. So, I think this is a good contribution. In fact, I wish some of the managers in our industry had these insights...

Having said that, I believe there is a difference between "doing" drug discovery and "describing a high-level view of it". Two different things; KC did a nice job at the latter.

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18. bad wolf on July 15, 2014 3:58 PM writes...

i like that you can always count on a smart-ass answer from Lyle no matter what the question.

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19. Anonymous on July 15, 2014 4:01 PM writes...

The worst thing about the Accepted Articles section, is when you see a title that could potentially scoop your project and you have to wait for the "Coming Soon" to turn into "Published Online" to find out. Waiting for it isn't fun- it happened to me. ACIE does this, but JACS (mercifully?) puts it online right away.

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20. z on July 15, 2014 4:25 PM writes...

Bad wolf, I suspect a large number of people read the ASAP versions of literature using RSS feeds or some other delivery method. I'm not sure why you feel like this is a bad thing. Is there any advantage to waiting for an article to officially appear in an issue?

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21. Anonymous on July 15, 2014 4:30 PM writes...

@17, I think perhaps a reason why some of us industry veterans find KC's review a bit strange is the fact that what he says is quite sensible, executing upon it given the current state of the industry is quite another story. If one could remove the layers of useless "management", waste, and incompetence in pharma and let us scientists do what we do, our industry would have an entirely different outlook.

KC has no direct experience with working within the constraints of a company... which, at least my opinion, is possibly the most challenging part of drug discovery today. Agreed, he is very sensible and raises some good points, but it's like he's living in la-la land.

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22. Kazoo Chemist on July 15, 2014 4:30 PM writes...

@17.

I haven't read the article because I do not have access to the electronic edition. However, I would have to agree with your position in principle.

If KCN (nice initials for a chemist) gets the details right as you indicate, then I wholeheartedly support his publishing the article. There are many academic chemists who have no clue about what is required for a viable drug discovery program. Unfortunately, they are probably not about to bother reading an article written by someone from Pharma who they have never heard of. If the KCN name gets their attention and they learn a few of the hard facts of life about how to critically evaluate their own programs it is all for the better. I doubt that the intent was to preach to the pharmaceutical choir, but to provide some insights for those who do not have exposure to the broad range of disciplines involved in drug discovery.

Besides, do any of the naysayers really think that KCN has never been intimately involved with a big Pharma drug discovery/development program??? Do they believe that he has no clue what it takes to evaluate drug candidates as they progress from discovery towards the clinic? I am certain that he has a wealth of first hand knowledge in this regard, perhaps more than many who actually work in Pharma. Anyone with current information care to list the companies he consults for?

Permalink to Comment

23. bad wolf on July 15, 2014 4:32 PM writes...

Well, it's just an organizational thing with me. The final versions are a little more systematic and categorized. Also it seems easier to miss an ASAP in the roll.

I just get the feeling that people have moved to a "i've got to read this first" system when you're usually looking at a week or two's difference. Not that i would accuse folks in the sciences of one-upsmanship.

Permalink to Comment

24. Anonymous on July 15, 2014 4:34 PM writes...

@22, without a doubt KC has been involved in drug discovery/development programs. I have not had him in as a consultant, but have had other big names in. But intimately involved? I'm not so sure about that.

As an add-on to my comment in post #21, he may see data from various drug discovery programs, but seeing the data versus actually being part of a team that is trying to push (or kill) a program is VERY different for a consultant vs. a team member (or team lead).

Permalink to Comment

25. Kazoochemist on July 15, 2014 5:01 PM writes...

@24

My experience has been with a group of chemistry consultants who were well versed in all aspects of the drug discovery process. Perhaps your consultants were a bit more narrowly focused. We always had organic chemistry consultants on the panel involved with annual or longer-period reviews of the research portfolio. That is probably more of a reflection of the regard our research group placed on chemistry.

I guess it depends on the personal interests of the consultant and just how much interest they have in aspects of drug discovery outside their own area of expertise. Without personally sitting down with KCN to discuss the topic, my gut tells me he has much more knowledge than many of the comments here would suggest.

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26. annon on July 15, 2014 5:11 PM writes...

Silvermsn'a example is described by only one word: Lucky.

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27. Barney Feaherson on July 15, 2014 5:11 PM writes...

@7
I empathize with you-myself with 28 years in process chemistry and out on the street for 4 years now. Not only is the problem H1B's at half of our age but the fact that hiring decisions are now made by absolutely incompetent HR departments who don't know a test tube from a Myers-Brigg test. I spoke to a recruiter the other day about the new wave of "behavioral interviewing" and offered her the opinion that that is the worst way to identify talent. To which she replied, "We use it to identify the soft skills". After vomiting, I suggested to her that maybe that perhaps that is why the pharmaceutical industry is taking the pipe.

Permalink to Comment

28. Barney Feaherson on July 15, 2014 5:13 PM writes...

@7
I empathize with you-myself with 28 years in process chemistry and out on the street for 4 years now. Not only is the problem H1B's at half of our age but the fact that hiring decisions are now made by absolutely incompetent HR departments who don't know a test tube from a Myers-Brigg test. I spoke to a recruiter the other day about the new wave of "behavioral interviewing" and offered her the opinion that that is the worst way to identify talent. To which she replied, "We use it to identify the soft skills". After vomiting, I suggested to her that maybe that perhaps that is why the pharmaceutical industry is taking the pipe.

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29. Lyle Langley on July 15, 2014 10:02 PM writes...

Sorry, Bad Wolf, didn't mean to hurt your feelings. Just stating what we all do in the 21st century. Now, that's a smart ass answer.

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30. Anonymous on July 16, 2014 3:43 AM writes...

From the paper:

'10. Develop systematically novel structural motifs to replace
excess aromatic moieties within drug candidates as
a means to achieve improved pharmacological properties.

11. Expand molecular space for chemical biology and drug
discovery studies through discovery and development of
new synthetic methods and strategies.

16. Place more emphasis on creativity and imagination at the
discovery and optimization phase rather than shortcuts,
unrealistic deadlines, and pressures that inevitably lead to
most-likely-to-fail, rather than -succeed clinical candidates.'

I think some of these issues are caused by the way people like KC educate chemists in the first place!

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31. anonymous on July 16, 2014 5:44 AM writes...

@26 - Dr. Silverman may indeed be "lucky" but that does NOT mean that he isn't a superb Medicinal Chemist (and a pretty damn good biochemist as well).
An Admirerer

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32. Anonymous on July 16, 2014 7:11 AM writes...

There have been many recent Pipeline threads about fraud, deception, retractions, and other problems in the scientific (chemistry, life sci) labs and literature. I have heard many stories about some KCN claims and know a KCN student who used to joke about how yields were adjusted in his publications to make them look better. The justification was that KCN was sure the yields would be higher with more time and effort ... so why bother with the time and effort?

IMO, falsification and wishful thinking is not the best approach to "Advancing the Drug Discovery and Development Process" ... but I have seen how it works wonders for "Advancing One's Professional Career" (in academia and industry).

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33. NH_chem on July 16, 2014 7:34 AM writes...

My experience with KC goes way back when his graduate student presented a paper at a National ACS meeting after mine on the same topic (specifically C-Glycosides from glycosyl fluorides). When discussing with this fellow graduate student at the mixer later, I asked about the stability of their fluorides as I noticed some stability issues and spoke about them.

He told me this "KC doesn't allow us to speak about things like that. We can only say that everything is perfect". Enough said......

Permalink to Comment

34. NH-Chem on July 16, 2014 7:44 AM writes...

@32 You are spot on. The graduate student I spoke to told me (after his 3rd beer) that his yields were based on rounding up on small scale reactions to allow for a yield that was "acceptable to KC".

I take great pride that everyone who repeated my procedures that were published were able to reproduce them exactly as published. That was the joy of attendance at the ACS national meetings for several years. Of course, we all lamented that one could never reproduce a KC paper.....

Permalink to Comment

35. petros on July 16, 2014 8:08 AM writes...

Well inflated yields in the papers of eminent chemists started many years before someweher close to where Derek works

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36. Anonymous on July 16, 2014 8:16 AM writes...

Despite my poor experience in this field, I always considered a yield +/- 5 to 7%, regarding the authors, the reaction and my own work.

Does it really matter ? 5% difference is acceptable. What you expect is the desired product, with a "precise-enough" procedure to get it.

If these affirmations were true (About KCN's students), it would be a +20 to 30% increase, which is to me, a true falsification. Yes.

Permalink to Comment

37. Anonymous on July 16, 2014 8:38 AM writes...

#27 - I think you need to talk to a different recruiter. I made the switch from pharma research into a different field and am now in management. I absolutely do use behavioral interviewing to find candidates, but it's not just looking for the "soft skills". The best predictor of future performance is past performance. Anyone can put whatever the heck they want on a resume - but you need to really probe in a behavioral interviewing situation to find out whether they know what they're talking about and if they're telling the truth. I should point out that this takes a skilled interviewer, and the vast majority of managers have never been properly trained in how to conduct a behavioral interview.

While behavioral interviewing can probe a candidate's technical knowledge, the "soft skills" are also important. Without good communication and team chemistry, it's all too easy to end up with a group of contributors who perform well individually, but can't deliver results as a team!

Permalink to Comment

38. Anonymous on July 16, 2014 8:47 AM writes...

#27 - Something else I neglected to mention. I understand where you're coming from. I've seen too many HR generalists who use Myers-Brigg as a hiring/firing/promoting criteria, who are apparently unaware that it's real value is about identifying different communication styles. Nothing ticks me off more than a 20-something HR generalist who doesn't have a team of 10 direct reports, no management experience, and doesn't have to worry about a budget telling a director (or first line manager, for that matter), what they should be doing!

#7/#27 - I actually had one of my managers come into my office yesterday to discuss a candidate and she wanted to remove them from consideration because they were "overqualified". I've heard that excuse too many times - it makes my head want to explode! (Really? Weren't you just complaining about the lack of qualified candidates? If someone is overqualified, doesn't that by definition mean that they're qualified? Maybe you should reconsider not hiring "overqualifieds".)

Permalink to Comment

39. Cato the Elder on July 16, 2014 8:54 AM writes...

@34 That kind of yield BS is epidemic in organic labs, not just in KC's lab. In my opinion, yields should only be considered as "low" (20-40%), "medium" (50-70%) or "high" (80-90%).

Permalink to Comment

40. An Old Chemist on July 16, 2014 10:21 AM writes...

Arun Ghosh of Purdue university, the drug Darunavir is named after him.

Permalink to Comment

41. ab on July 16, 2014 10:50 AM writes...

On the topic at hand, which is KCN's paper, it reads like a catalog of all possible predictive tools, synthetic methods, and target modalities (I'm not sure what the average number of commas per sentence is in this paper, but it is HIGH), and then says do all of them more and we'll be more successful as medicinal chemists. Well yeah, no $hit. The problem with flying at 40k' (i.e where KCN sits) is that you don't see the real issues that present themselves in a real med chem lab where the rubber meets the road. We are always time and resource constrained. That is a fact of life in industry (and academia, for that matter): we have a bottom line that depends on efficient use of resources. Given that reality, we can't just "run more experiments" to "completely validate a target." Instead, we have to ask the RIGHT questions and run the RIGHT experiments to answer them as completely as practicle. This is very different from asking ALL of the questions and then running ALL of the experiments to answer them completely. Making the RIGHT decisions based on limited data is actually really, really challenging and requires real talent and insight. But if you have people who can do that, you improve your POS substantially.

Permalink to Comment

42. Anonymous on July 16, 2014 11:19 AM writes...

@25, interesting to hear. I've spent a few years working in discovery chemistry, but the majority has been in both early and late development. We often had several consultants dive deep into programs at quarterly reviews (at the 3 companies I have worked at), but they were all retired "senior-level" individuals from biotech/pharma.

Permalink to Comment

43. Barney Featherson on July 16, 2014 11:31 AM writes...

@37
Soft skills are bullshit. I always hired on the basis of someone who could make the chemicals. Anyone who was a bullshit artist (read soft skills) was immediately relegated to the trash heap.

@38
I agree-the overqualified moniker is ridiculous. I was told to my face one day by a(n) HR person that everyone was intimidated by my resume, hence I would not be called in for an interview. It is the old HR bullshit theme that if you are not challenged you will not perform well. Guess what, some exceptionally skilled people are out there who are unemployed because of the errant HR policies in existence and they need a job and they will perform superbly if only given a chance.

Permalink to Comment

44. Anon on July 16, 2014 12:21 PM writes...

@22

KCN is co-founder of Array Biopharma, who I used to work for, for whatever that is worth.

Permalink to Comment

45. Lyle Langley on July 16, 2014 12:29 PM writes...

There are only a couple of instances where being over-qualified is an issue. The first being when the job market is pretty good, hire someone that is over-qualified and more than likely they get bored and start looking elsewhere (not really applicable now). And the second being when they are a-holes. Nothing worse than an over-qualified, a-hole - they will make everyone's life miserable.

Funny thing is, and something most HR departments simply don't get, there are many over-qualified people in their jobs because it is difficult to get properly promoted in your current job. You have to do your job and the next job before promotion (i.e., over-qualified for current position). Used to be when the market was decent you got promoted by going to a different company.

Permalink to Comment

46. Anonymous on July 16, 2014 1:49 PM writes...

@45, Your comment "You have to do your job and the next job before promotion (i.e., over-qualified for current position)" will surely give some industry veterans a chuckle. From my perspective from working in huge pharma companies to tiny biotechs, that's literally the opposite of what one needs to do to get promoted. If a person does their job extremely well and their bosses job extremely well, there's a great chance they'll be not getting a promotion any time in the near future and perhaps even shown the door.

People are overqualified in pharma, because they are a perceived threat to their manager or manager's manager and held down. Be mediocre and your boss will love you since s/he can include helping "guide and mentor" you on her/his annual goals and s/he won't ever worry about being replaced by you.

Permalink to Comment

47. Lyle Langley on July 16, 2014 2:26 PM writes...

@46, Anonymous...

I get what you are saying, but coming from a non-linear type of reporting scheme, getting promoted didn't mean getting your bosses job. Never belonged to a straight-lined system (nor many others that were). My direct reports were not going to take my job; but I couldn't promote them because of the items I outlined.

Permalink to Comment

48. Nick K on July 16, 2014 8:33 PM writes...

#33 and following posts: Many moons ago I worked at Penn when KC was still there. It was common knowledge that his methodology was flaky and his yields were fictitious.

Permalink to Comment

49. Half century on July 17, 2014 4:09 AM writes...

@32 et seq. The key compound in any medchem paper or patent worth having will pretty soon be checked out by competitor companies, whereas there's little kudos in replicating a total synthesis.

So to an awkward question - what proportion of published total synthesis, including work directed by the greatest and the goodest, could not be replicated by ones skilled in the art (less than 1%, 1-5%, greater than 5%?). Just asking.

Permalink to Comment

50. Rock on July 17, 2014 7:17 AM writes...

Reasonable perspective but fairly pedestrian from an industry point of view. Could have used some editing to cut down on the use of the words "ideally" and "indeed" though (I lost count!). I wonder if this paper is a filler to keep his publication numbers up until the maitotoxin paper(s) come out. Haven't seen much from KCN recently....

Permalink to Comment

51. NH_chem on July 17, 2014 8:02 AM writes...

@49 I guess it comes down to ethics and morals. I was fortunate to have a very ethical graduate advisor. I personally am disgusted by scientists that do not report the actual results. Then again, it doesn't appear to matter to those trying to make a name for themselves. Sad.....

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52. Anonymous on July 17, 2014 9:26 AM writes...

I can't help but wonder ... Is KCN feeling hurt and under attack because so many people in a popular and professional public forum think that portions of his work are questionable or is KCN the kind of guy to be laughing at us from his cushy pulpit at Rice and thinking "What a bunch of morons. I'm here, rich and famous and you're not."

Or does he stand by earlier claims and deny any wrongdoing even though many students have told stories about KCN changing their submitted results to more acceptable publishable claims?

Does KCN know how many students elsewhere couldn't reproduce his claims and suffered the consequences when their PI judged them stupid or incompetent and not good enough?

Where's Hudlicky to comment on this stuff?

Permalink to Comment

53. Anonymous on July 17, 2014 12:26 PM writes...

#44

As a former employee as well, he was listed as a 'co-founder' for his name cache only, mainly due to his ties to a few of the other founders, namely Piscopio and Koch. He had very little to do with Array other than getting his founders shares and selling them soon after they went public.

Permalink to Comment

54. MoMo on July 17, 2014 5:00 PM writes...

Its just KC jumping on the "translational" bandwagon. These trends happen from time to time, and really do nothing but obfuscate real drug discovery research being studied and performed.

I lump "translational" efforts into the same category as combichem, everything "omics" and Unicorn or Yeti hunting. So be careful what goes on your resumes.

But this is America and if you want to spend time reading reviews by Old Brains thats up to you.

I like the works coming out of newer brains these days anyway.

Permalink to Comment

55. volatile on July 19, 2014 8:21 PM writes...

Despite the general condemnation of this article, very few here actually attempt to discuss the paper on its merits (or lack of) and rather choose to debase KCN's character and ethics instead, it's a little pathetic.

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56. navarro on July 20, 2014 10:09 AM writes...

@43

obviously you've never hired a highly qualified a**hole or your attitude about soft skills wouldn't be so dogmatic.

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57. Nick K on July 21, 2014 9:59 PM writes...

56 navarro: I think the reason for the animus towards KC on this blog is that his dishonesty has damaged the integrity of the chemical literature. He's not alone, of course.

Permalink to Comment

58. Frankie goes to Hollywood on July 29, 2014 7:41 PM writes...

Is kc the issue or is it the system in which he operates?

The system gets the behavior it rewards.

Permalink to Comment

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