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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: Twitter: Dereklowe

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« Short Items: India, Sanjay Gupta, Satori Pharmaceuticals | Main | Poor Equipment Revisited »

January 9, 2009

The Perils of Poor Equipment

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Posted by Derek

The late Peter Medawar once wrote about resources and funding in research, and pointed out something that he thought did a lot more harm than good: various romantic anecdotes of people making do with ancient equipment, of great discoveries made with castoffs and antiques. While he didn’t deny that these were possible, and admitted that you had to do the best with what you had, he held that (1) this sort of thing was getting harder every year as science advanced, and (2) while it was possible to do good work under these conditions, it surely wasn’t desirable.

His most interesting point was that lack of equipment ends up affecting the way that you think about your research. It’s not like people with insufficient resources sit around all day thinking of experiments that they can’t run and can’t analyze. If you know, in the back of your mind and in your heart, that there’s no way to do certain experiments, then you won’t even think about them. Your brain learns to censor out such things. This limits your ability to work out the consequences of your hypotheses, and could cause you to miss something important.

Imagine, say, that you’re working on some idea that requires you to find very small amounts of different compounds in a final mixture. A good LC/MS machine would seem to be the solution for that, but what if you don’t have access to one? You can spend a lot of time thinking about a workaround, which is mental effort that could (ideally) be better applied elsewhere. And if you had the LC/MS at your disposal, you might be led to start thinking about the fragmentation behavior of your compounds or the like, which could lead you to some new ideas or insights – ones that you wouldn’t have if you’d had to immediately cross off the whole area.

If you’re in a resource-limited situation, then, you’ll probably try to carefully pick out problems that can actually be well addressed with what you have. That’s a good strategy, but it’s not always a possible one. Huge areas of research can be marked off-limits by the lack of key pieces of equipment, and by the time you’ve worked out what’s possible, there may not be anything interesting or important left inside your fence. Medawar’s point was that being stuck inside such a perimeter would not only hurt the way that you did your work, but could eventually do damage to the way that you thought.

It occurs to me that this is similar to George Orwell's claim in "Politics and the English Language" that long exposure to cheap, misleading political rhetoric could damage a person's ability to think clearly. "But if thought corrupts language, language can also corrupt thought". There may be other connections between Orwell's points and scientific thinking. . .definitely a subject for a future post.

In fairness, I should mention that the flip side of this situation isn’t necessarily the best situation, either. Having everything you need at your disposal can make some researchers very productive – and can make others lazy. Everyone has stories of beautifully appointed labs that never seem to turn out anything interesting. There’s danger in that direction, too, but it’s of a different kind. . .

Comments (35) + TrackBacks (0) | Category: Academia (vs. Industry) | Life in the Drug Labs | Who Discovers and Why


1. Fred on January 9, 2009 9:35 AM writes...

"You can spend a lot of time thinking about a workaround, which is mental effort that could (ideally) be better applied elsewhere."

One of your better posts, Derek. But it's across the board: companies that are cheap about equipment also try adventures like "cheap" chinese CRO's and then wonder why they aren't getting results any faster than when they were doing things right. Research is like a cat; it moves at its own pace, but a GOOD cat is well-fed by what it catches. Look at the combo adventure: you get more compounds, but less purity and structural diversity. By the measure of project progress, it's just about a "wash" compared to traditional chemistry.

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2. NH_chem on January 9, 2009 9:51 AM writes...

Too many chemists have lost sight of great, simple techniques that also happen to be cheap. One of the most underutilized techniques is TLC. While LS/MS and HPLC give certain results, one can often get valuable info from a simple TLC plate.

Case in point- carbohydrates char on a TLC plate when hit with sulfuric/EtOH and heated. The LC/MS can't do that and this takes all of one minute.

Sometimes all the fancy toys can't replace good lab experience. Working on the cheap is fine if you are good.

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3. Derek Lowe on January 9, 2009 10:07 AM writes...

Nothing against cheap techniques that do the job! There are many times when TLC (for example) gives you what you need to know, quickly.

I think the best world is one where you have access to both the cheap and the expensive techniques, and can use the one that's best suited to the job. You usually don't run across situations where someone is forced into using only the expensive stuff, though - the limits are the other way around, where someone's forced into using only the cheap methods.

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4. Cindy on January 9, 2009 10:23 AM writes...

University Profs are notorious for abusing their students with low-tech equipment. Many faculty are cheap, or have the attitude of "I did it that way, hence so will you".

Unfortunately, you get no credit for this in real life, as students from the 'smarter' labs race to the finish with automated sampling and analysis, while you waste time. You can waste years in such a fashion.

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5. CMC Guy on January 9, 2009 11:04 AM writes...

#2 NH_Chem is on target and it is not due to access of old vs. new it is more the mindset of being enamored with all the fancy new instruments that chemists don't use and often ignore possible simpler techniques (some of this starts in grad school and then gets worse when join industry labs).

IMO working in a "disadvantaged lab/school/country" can generate more effective researchers who learn how to solve problems regardless of resources. If people are truly mentally censoring their activities because of equipment which prevent doing certain experiments I would worry as they should be devising ways to achieve the results by different means or seeking out collaborations so that can pursue avenues. Isn't that what Science is about?

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6. rhodium on January 9, 2009 12:06 PM writes...

What access to (or even the existence of) powerful analytical tools does change is the time spent in thinking about clever solutions to problems. Classic biochemistry and chemistry papers from 1900-1960 often provide wonderful examples of clever experimental designs and logical flows that overcome experimental limitations (all organic chemists will now be thinking of Emil Fischer's determination of glucose's configuration). Perhaps cleverness in analysis is still alive in messier disciplines like immunology but in small molecule organic chemistry and single protein biochemistry brute force rules.

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7. Anonymous on January 9, 2009 12:09 PM writes...

CMC Guy:

I agree. As a fairly young medicinal chemist (35yrs old) having worked in the industry for 12 years now, I have always been "minimalistic" in my choice of using fancy equipment. It isn't as though I do not know how to use them, the majority of the time it is not needed. Many pieces of equipment fall under the "nice to have" category.

It has always been my opinion that my generation is much less intelligent than the previous generations due to modern inventions. Who needs to commit advanced mathematics to memory anymore, just use a computer. Who needs to understand organic chemistry, arrow pushing, etc. Just look it up in Scifinder.

I guess my point is that modernizing does come with some consequences.

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8. KC on January 9, 2009 12:27 PM writes...

I would agree with Derek, but with the massive caveat that there probably are many situations where this is true, but there's nothing that can be done. Poorly funded groups, or pretty much any lab in academia, has different budget realities than those in a more secure fiscal situation. Assuming what you say is accurate, what on earth is Jane or Joe Assistant Professor supposed to do about it? They can't just plunk down funding they don't have for that LC/MS.

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9. Anonymous on January 9, 2009 12:44 PM writes...

My first job was at a severely resource-limited company. It was a good opportunity to learn more about old-school wet chemical analytical methods. My undergrad analyical course only covered instrumental methods, so everything I knew about wet-chemical methonds I learned in freshman gen chem. I was surprised to find out that professional chemists used TLC; I always thought it was just an instructional aid for undergrad teaching labs.

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10. G on January 9, 2009 1:07 PM writes...

Aside from laziness, many well-funded labs are not productive because they've become so enamored with their equipment that they overlook simple and elegant, yet old-fashioned, answers to their questions.

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11. GregTheOrganiker on January 9, 2009 1:57 PM writes...

I am surprised that no one has mentioned the difficulty of getting things published in top-shelf journals without methods like LC/MS or HPLC. Every year, the number of accepted articles without such characterization decreases, and hi-res MS is now an absolute requirement for some. I understand that these "advanced" methods are often the surest; but do we not, as a community, say what is necessary technologically by those publications we value most?

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12. The Inorganic Gardener on January 9, 2009 2:11 PM writes...

I did much of my early training in a "disadvantaged" lab (the kind where you wash out plastic disposables and re-use them and buy technical-grade everything then recrystalise it yourself etc) so I'm a big believer in the fact that you can do a lot with very little, if you put your mind to it.

Take for example measuring the concentrations of various compounds in solution. You could use HPLC and it'll all be automated and very accurate, but for most purposes, you can get away with a colourimetric assay (which probably involves nasty chemicaks and takes a half day) which gives you a result to the nearest mmol.

The best solutions are always the most simple, elegant ones. I recently re-read Krebs' original paper on the tricarboxylic acid cycle which was all done using Warburg apparatus, a pigeon procured from the local butcher, 14C-labeled substrates and TLC. Thesedays, folk trying to answer the same questions as Krebs would immediately say "oh we can't do that work here because we don't have NMR" "or we can't do that work here because we have NMR but I don't know how to use it" - well learn!!! You really, really don't need fancy equipment for most applications. Sure things will take much, much longer when done The Old School way, but they will yield similar results for most applications.

What's the obsession with everything have to come in kit-format these days too? It's all pre-made solutions and neatly aliquotted things in vials. Save a fortune - make your own solutions!


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13. Steve on January 9, 2009 2:23 PM writes...

Interesting... as a molecular biology graduate student I was nickel and dimed by my advisor. As a consequence, I designed experiments to avoid buying some reagents. Looking back, it was a total inefficient use of time to get substandard results. For a bit more money, I could have completed some experiments faster and got more interpretable results in the first shot. There are just some "expensive" things that you can't replace. Enzymes can't be replaced with other techniques. A restriction map doesn't replace real sequence data.

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14. Eric on January 9, 2009 2:25 PM writes...

The lack of good equipment, on the other hand, can spur a nice collaboration with a lab that does have a nice specialty instrument or specializes in a particular technique. I'd never attempt to crystallize any protein without the air tables and environmental controls that the crystallography labs have, and at that point, I might as well ask the help of someone who knows what they're doing anyway (it'll get done faster, and I learn from the experience without flailing as much).

As for kits, I used to think that kits were a waste of money (and some still are...e.g. precast agarose gels), but I've changed my mind over the years. Kits can save a lot of time troubleshooting protocols and reagents, which a lot of times is much more expensive than the kit itself. A grad student or a postdoc is tens of thousands of dollars a year in costs. That's on the order of $100 per day of labor costs; spending a week or even a month troubleshooting something instead of spending $100 or even $500 to get something done fast and easy is idiotic.

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15. The Inorganic Gardener on January 9, 2009 2:37 PM writes...

Steve - you can save a lot of money in molecular biology. I know some top labs who regularly publish amazing work in the high-end journals and who express and purify their own Taq and restriction enzymes to save cash so they can spend it elsewhere.

Eric - It's the kits like precast agarose gels, pre-made gel loading dye, ATP-determination kits etc which I don't like. Sure, for RNA extraction or TA cloning, you'd be a fool not to use a kit 99% of the time, but I worry that people use them with no idea of what they're actually doing. I've a friend who is a bigger academic fascist than I am and her favorite viva questions are things like "Ok, so this RNAEasy kit - how does it work?", "What does RNALater do then?", "Explain how cloning DNA works" etc etc etc and she reports that very few candidates in recent years seem to have a clue.


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16. Hap on January 9, 2009 2:44 PM writes...

I think the question (which I don't know have the data to answer) is whether more of the people who come from labs that make do end up becoming good scientists than those who come from labs with average or above average equipment levels. The people who come out of labs with insufficient equipment might be able to think their way around a problem, but there might be significantly fewer of them (which means much of the effort you are spending on training students is going to waste). If you're only selecting the best students from labs with less equipment, then you need to compare students of similar ability out of both types of labs.

In general, I think professors treat grad student time as an infinite resource (unless they're working on something that is highly time-dependent like a first-to-molecule total synthesis). Places with less money are probably more likely to replace money with graduate student time - while that gives you more training, it is not necessarily a good technique when working out of graduate school, where time is not infinite and is costly enough in resources to be conserved. If you can do elegant experiments that take thrice as long as brute force experiments with better equipment, brute force might work better.

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17. Chrispy on January 9, 2009 3:32 PM writes...

I don't get it. Relative to the questions we want to know the answers to, even the best equipment is severely limited. If you develop clever experimental solutions using good equipment you just get to answer harder questions.

The best scientists I have known have come from labs with the best equipment and have still ended up cobbling stuff together because they're working at the cutting edge.

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18. Jose on January 9, 2009 4:22 PM writes...

I think being forced to MacGyver things a little teaches you quite a lot of good skills. However, when that becomes the main time sink, problems exist. For a good illustration how much our skills as chemists have deteriorated since the golden age, check out Williams' recent quinine paper (Angew Intl Edt, 2008, 47, 1736-1740). The supp info is nothing short of stunning- running everything with 1940's techniques.

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19. CMC Guy on January 9, 2009 4:53 PM writes...

#16 Hap its not a numbers game as is more about quality of education/experience and how to motivate innovation, both aspects which are hard to measure and compare. While subject gone over here previously the frequent advantages of people from Big Name Schools/Labs (thus usually having best equipment) often fades quickly. Learning how to think seems to be less of a focus than accumulation of bunch facts these days. As noted above doing Math on Computers or running pre-made assay Kits may useful skills but if knowledge on underlying elements weak then value lessened. At the same time, unless the goal is specifically to train, it is often ridiculous not to use available resources (buy or make chemical starting material) to make work progress. Typically less problem in industry where time vs money viewed/driven differently that in academia.

#17 Chrispy points are well expressed. To me its that good people will usually succeed regardless but given proper tools they can do even more.

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20. Skeptic on January 9, 2009 5:31 PM writes...

The topic should be renamed:

"The Perils of the Industrial Chemist Mindset"

And somewhere in about the last fifteen minutes, an announcement to cure that problem has occured: "Interdisciplinary Research Centre in [Insert city name here] Planned".

Thats where you sit an Industrial Chemist beside a Statistical Physicist and an Abstract Mathematician. Now will that enhance productivity? Nope.

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21. zts on January 9, 2009 6:47 PM writes...

I think the bottom line should be: Use the best equipment you can, meaning whatever gets the job done in the most efficient and effective fashion. The best equipment may not be the most expensive, technologically-advanced equipment, although it often is. Be pragmatic--understand all the options and evaluate them according to your needs.

Yes, there are times a TLC is better than an LC-MS, so, in those times, use TLC to monitor your reaction. Most of the time, it isn't, so use LC-MS. Use what works the best. It is often true that people can make great scientific discoveries without the latest and greatest technology, but it takes a lot longer, and time is important and expensive. And sometimes you really do need the technology.

It is valuable to learn to do things the old-fashioned way, if only in an educational setting. It can help you to understand better what is really going on, to be able to think more critically about what you are doing, troubleshoot, etc. People do need to understand, at least at some level, what is going on in the otherwise black box. It was probably valuable for me to have done flash chromatography by hand with glass columns in grad school, but I plan to never do that again in my career.

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22. Anonymous BMS Researcher on January 9, 2009 7:27 PM writes...

If you think dollars are tight in rich-world academia, imagine what life is like in developing countries. A grad school friend of mine spent a while doing field work on an island in the South Pacific; because he was a visitor from the US they let him use the best microscope they had -- which he said we would not use in the Freshman labs.

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23. ss on January 9, 2009 8:57 PM writes...

One of the cheapest methods of finding out the composition of an unknown distilled solvent mixture (distilled Column chromatography eluent)was taught to me in my first job by an oldtimer. While I wanted to use the GC, he just had a precalibrated Rfs of a known compound using differnet solvent percentages and just did the TLC of the known compound with the unknown distilled solvent and using the Rf was able to determine the composition of the distilled solvent mixture. He said that in his time, GC was an expensive instrument, not readily available.

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24. RTW on January 9, 2009 11:06 PM writes...

Re: 2.NH_Chem, 21. Zts

I hear you guys, but take exception with zts assertion that LC-MS is better most if the time. That's not been my experience over the past 20+ years. And TLC when done correctly only takes a few mins. to determine a great deal of information.

I think the issue is that few people coming out of chemistry programs today know how to run TLC or develop silica or alumina separation methods very well. No one took the time to really teach them about the method. Probably the most instruction anyone got was in their first organic chemistry lab if they where lucky. Otherwise they got a couple of quick pointers in the lab from another grad student, or postdoc, but most hardly practiced it for its potential. I guess I was lucky as I had a professor that was very good at it and took the time to teach me to be good at it as well. I was excellent at doing TLC work. Could practically separate anything with it, and apply the method directly to preparative separations of various scales. I kept several sprays that colored differently for changes in functional groups. Could identify products and reactants pretty fast in many cases. Additionally I would sometimes combine the TLC method with rapid LC-MS. A favorite technique was to separate a sample of my reaction mixture via TLC. Scrap off the spot and treat the silica with a polar solvent, filter well then run an MS to identify the mass of the spot. This was a very rapid means of identifying a lot of the reaction components. Following a reaction to completion, and finally applying the separation method directly to semi preparative medium or flash column chromatography conditions. Can't easily convert your LC-MS conditions to preparative LC isolation....

Now I use to repair and maintain LS-MS instruments and I can tell you they are touchy things, methods don't scale, and its very time consuming to develop good LC methods. And people treat these instruments as trash cans injecting toxic waste into them mucking them up constantly. They are often down more often than they are up and operational.

TLC due to its rapid development times, potential to get functional group information from derivatizing sprays, and the ability to dis-orb compound from the stationary phase (silica or alumina) and run an MS on a spot no less.... I think makes TLC a much more powerful tool that everyone with practice can learn to do very effectively.

Additionally. How many of you know how to determine if an unknown organic molecule contains a halogen without access to an MS? I do. When is the last time any of you used an IR and generated information about the potential functional groups in their molecule? Have to depend on Multi dimensional NMR methods now a days I guess?

Of course I use to teach a lab course in qualitative organic analysis. In fact let me recommend "The Systematic Identification of Organic Compounds" by Shriner, Fuson, Curtin and Morrill. Good book - I have others packed away I have not referred to in a long time. But there is a lot to be said by using old wet chemical methods. Our chemical forefathers managed to figure out the structures of some pretty hairy molecules without a lot of fancy equipment after all.

And finally to that was a very interesting method. I will have to remember that as GC's are very rare in even most industrial Pharma labs. Might be one somewhere in the department but changes are good its not working.!!

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25. RTW on January 9, 2009 11:08 PM writes...

Sorry about the duplicate. Derek can you delete one please?

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26. Anonymous on January 10, 2009 12:24 AM writes...

Re: #26, RTW.

I certainly agree with you that TLC can be a very powerful tool. You can gain a lot of information from it, and a lot of people (myself included) probably don't know how to use it to its full potential. However, I still think that LC-MS is, most of the time, more powerful.

An LC-MS may take longer to run than a TLC, depending on the method and queue, but usually not much longer. Knowing the mass of each of the components of your reaction mixture can save quite a bit of time in the long run. When I had to rely on TLC alone, I spent a lot of time working up and purifying failed reactions. Sometimes you can tell by TLC when a reaction isn't working, but a lot of times there is a new spot, or, worse, several spots, with reasonable Rf's. So work it up. Look at the crude NMR, sometimes you can tell. Sometimes it is a mess and you can't tell--there could be some pdt. So run the column. Get a couple of different compounds off, not really sure which ones to go after, so go after all of them. Concentrate them down, take NMRs. OK, no pdt, these by-pdts aren't that interesting, so throw them out. Now if I had LC-MS, I would have gotten all that information right away, thrown the reaction out, and gotten on with things.

Things aren't always that neat and tidy. Sometimes TLC will tell you what you need to know, and sometimes LC-MS won't. Sometimes the compounds are not UV active. Sometimes the peaks don't show any mass, or you only see fragments. Sometimes the peaks do show the correct mass but it isn't the right product. You still have to think about what you're doing, and think about what is going on in your reaction, and exercise judgment. Most of the time, the LC-MS will give you a pretty good idea of whether your reaction is working or not, and typically better and more quantitatively than TLC.

Translating LC-MS to flash chromatography: True, it does not always translate directly, but the LC-MS usually gives you a pretty good idea of the order in which compounds will elute and the relative intensities you expect to see on the UV trace. If you have automated chromatography systems, they run a gradient, so figuring out the proper solvent system to give good separation is less important. All you really need to know is will this move well on a 0-100% EtOAC-hexanes system, or should I switch to MeOH-DCM? Sometimes you know this intuitively from similar compounds you made, otherwise run a TLC to check.

Translating LC-MS to prep HPLC: Usually translates pretty well if you use the same kind of column on each.

Regarding LC-MS cost and maintenance: Yes, it is expensive, and takes a lot of work to maintain. But if you have the resources, I think it is worth it.

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27. bradley on January 10, 2009 12:42 AM writes...

how many university chemistry departments still have glass shops?

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28. processchemist on January 10, 2009 3:41 AM writes...

For sure in modern medchem LC-MS and a 400-600 Mhz NMR are almost indispensable. When you turn to process development are helpful too (assesment of identity of the impurities) but for In Process Control you need a good and FAST method. FTIR probes are wonderful, expensive things, but a well developed HPLC method (with 10-15 min of run time) or a TLC (both accepted by FDA) are the target.
A certain lack of hands on experience in some project managers from time to time causes in meetings statements like "What's the problem? You can perfectly monitor the reaction by HNMR"...

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29. The Inorganic Gardener on January 10, 2009 8:56 AM writes...

Bradley - we're fortunate here - we have a wonderful glassblower! Ironically, the Chemistry dept (where he is based) hardly use him but the Biology dept (over a mile away) use them all the time. I've saved a small fortune by having him make copies of glass fermentation equipment and columns which we have borrowed from the manufacturer for a "one week trial", by which time the glass guy has cloned them and we send the originals back and have saved hundreds of pounds.

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30. jt on January 10, 2009 4:40 PM writes...

Crystallization, mp, sublimation, IR, UV, distillation and others. Everytime I mention these methods my folks think I've flipped my lid...And people wonder why Pfe spends $9.6 E10/year for nothing.

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31. jt on January 10, 2009 4:47 PM writes...

Every time I mention something like crystallization, sublimation, distillation, mp, IR, UV and the like, my folks think I've flipped my lid. At the very same time, people wonder how Pfizer can spend $9.6 E9 without getting anything.

Is there any possibility these two conundrums are related?

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32. JSinger on January 10, 2009 11:55 PM writes...

I know some top labs who regularly publish amazing work in the high-end journals and who express and purify their own Taq and restriction enzymes to save cash so they can spend it elsewhere.

As someone else noted, this is the mentality that grad student and postdoc labor is infinite. What's the opportunity cost (in both time and subpar enzymes) of sinking top researchers into enzyme preps? That said, while the patent situation around Taq makes it lucrative to make yourself, I've never heard of anyone making restriction enzymes since the the 70's.

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33. NSD on January 11, 2009 6:25 PM writes...

Only one person so far has mentioned the situation facing researchers in developing countries. What we think of as "limited resources" may still be order of magnitude better than our colleagues in much of the world. Having worked in a lab in West Africa, I can attest that your view of what is possible is severely restricted when reagents take 6 months to arrive, disposable test tubes cannot be disposed of, and you have only one piece of mechanical equipment in your lab. You can't "just try things", and you may not always be able to replicate experiments because resources are so limited. It was this experience that led me to found Seeding Labs ( to use the surplus from our labs (yes, even the limited ones have surplus from time to time) to equip talented scientists working in developing countries.

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34. C Bailey on January 13, 2009 11:38 PM writes...

One of my professors claims that none of us has any conceptual understanding of how an NMR works partially because we don't have to do any of the programming since we have parameter files. On the other hand, I'd never EVER want to have to interpret some of the NMR spectra from the time that he was in grad school.

This is interesting because I come from a small liberal arts school that is more teaching oriented than research oriented, so I'm definitely used to thinking in terms of what is cheap. We don't have an LC-MS, and our HPLC is perpetually down.

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35. Hap on January 25, 2009 2:59 PM writes...

C+EN was discussing the funding crunch for small biotechs, and it seemed relevant here. One of the analysts believed that good ideas would survive the crunch, while bad ideas would go away (the lack of funding would be accelerate the evolution of companies and ideas). Another analyst counterargued, saying that it was likely that some good ideas would die along withe bad (because as he said, if companies knew ahead of time what would work, what they do wouldn't be called research). The ending quote bemoaned the lack of new companies, which might serve as another argument - making it hard for people to do research just means that they are less likely to do so, and that it will be harder to train people later, if you do get resources.

I interpreted this as a business analogy to the more resources/less resources training argument, and it seemed clear by implication what their opinions were.

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