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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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February 3, 2009

The Original Nanotechnology

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Posted by Derek

Organic chemists, my tribe, have accomplished a lot. But we’ve managed to convince people that we’ve accomplished even more than we have. The general assumption seems to be that we can pretty much make anything, given enough effort. Considering some of the awful molecules that have been made, I can see where that opinion comes from – mind you, as has been discussed around here, many of the toughest molecules have been made by terrible human-wave tactics and unscalable grad school conditions. But they have been made.

So, given unlimited time and money (and cruelty), I suppose it’s true that we can make most anything. But, as many spoilsports keep pointing out, these hideous natural product molecules that take us so long are also being made under much more impressive conditions. But not by us. That hit me when I was in graduate school myself, working on a macrolide antibiotic structure. Reading up on the stuff, I found that it had been isolated by culturing a bacterium from a soil sample taken from a Texas golf course. I got to thinking about that. Here I was, slaving away nights, days, weekends and holidays to get within hailing distance of the structure, and this prokaryote was sitting around in the dirt of the fourteenth green, listening to golfers curse while making my molecule at ambient temperature, in water, and at the same time doing everything else it needed to do to stay alive. Worth thinking about, it was.

I realized then what others had already been saying: that our best synthetic methods really didn’t stand up to what enzyme systems were capable of. Years of medicinal chemistry have done nothing to alter that opinion. Everyone in this line of work has seen what the liver enzymes can do to our carefully constructed molecules, reaching in and oxidizing them to make them sluice out in the urine more quickly. And those transformations are things that, for the most part, we just can’t do. Can you pick up a complex molecule and selectively put a para-hydroxyl on just one of its aryl rings? Nope, me neither. Can you make an epoxide out of benzene (without tearing everything else to shreds?) I doubt it; I sure can’t.

No, the more you know about chemistry, the more humble you feel when you look at enzymes. There’s no substitute for holding down the molecule and working on one part of it with hammer and tongs – it’s a totally different world than the bulk solution-phase stuff that we do in our reaction vessels. Enzymes are the original nanotechnology. They give us something to aspire to.

Comments (38) + TrackBacks (0) | Category: Chemical News


COMMENTS

1. MTK on February 3, 2009 9:15 AM writes...

I've sort of gone back and forth on this over the last 20 years.

1. Yields are often ridiculously low for some metabolites. Not nature's fault, since they don't have a lot of different starting materials.
2. Purities can be lousy also. There's a lot of stuff in those extracts of marine sponges.
3. Nature has had, by our reckoning, unlimited time. Billions of years in fact.
4. It can also have unlimited resources. Millions of little workers over thousands of generations around that 14th green for example.

No doubt, Mother Nature has done some incredible work, but it may have taken advantage of the nearly infinite time, resources, (and cruelty) that limit us.

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2. Retread on February 3, 2009 9:37 AM writes...

Sorry Einstein, God isn't a mathematician or a physicist. She's a chemist.

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3. Wavefunction on February 3, 2009 9:52 AM writes...

Interestingly I am reading a book by Robert Hazen on the origins of life where he makes an intriguing point about why we are not still remotely as good as nature; apart from the fact that Nature had the luxury of billions of years of evolution, Hazen is also of the opinion that we still have a less than rudimentary understanding of emergent phenomena which are key in the evolution of efficient biological systems.

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4. MedChem on February 3, 2009 11:19 AM writes...

And yet, we continue to ascribe these wonders to evolution and utterly exclude even the possibility of God. Very scientific and open-minded indeed. Consider this senario, my fellow chemists: that reaction of yours which refused to work no matter what conditions you tinker with. And you decide "to heck with it, I'll just keep stirring the darn thing for another billion years while flashing lightening through the flask. That's gotta work right? That's how we humans eventually came to be!!"

Please, I meant no insults to anyone.

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5. P on February 3, 2009 11:26 AM writes...

Speaking of natural products, any comment on Djerassi's letter to the editor in the latest C&E News? Ouch!

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6. RB Woodweird on February 3, 2009 11:28 AM writes...

MedChem, have you actually taken a look around God's green earth? Do you know what's going on inside your cells this very minute? A staggering collection of inefficient, half-assed, kludged-up processes, that's what. It is conclusive proof that no competent omnipotent intelligence had any hand in the matter.

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7. MedChem on February 3, 2009 11:59 AM writes...

RB,

Respectively, your premise was based on the assumption that a perfect human body/design is what God intended. In the context of my christian faith, the scriptures clearly point out that's not the case. However, the early humans did live to be over 900 years old, and then God decided to take that longevity away because of the prevalence of sins (ref: the Old Testament). Although our current body was never meant to be perfect by design, could this devine change of heart explain the more large scale biological imperfection and decay we see today? The Bible does also say that in Heaven we will be given new bodies which will never deteriate. I bet you'll find perfect biology then :)

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8. Fred on February 3, 2009 12:12 PM writes...

Is there really anything more than a semantic difference between "emergent phenomena" and "intelligent design"?
Do not both claim that the forces of nauture are "set up" to produce life?

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9. Jose on February 3, 2009 12:12 PM writes...

Sweet baby jesus! Not only is god omnipotent, and all powerful, he also builds perfect systems, and then deigns to *intentionally* build a even more staggeringly complex Rube Goldberg layer on top??

(don't feed the trolls. don't feed the trolls. don't feed the trolls. mantra for the day).

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10. CF on February 3, 2009 12:58 PM writes...

Does anyone know of any articles investigating (small) molecular structure space using concepts in facilitated variation?

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11. Hap on February 3, 2009 1:15 PM writes...

I thought that emergent phenomena were phenomena whose effects did not scale with size or time - they evolve in a way that can be explained mathematically, but don't relate predictably with variables we can readily see. Emergent phenomena aren't directed, just unpredictable (to us), but they can be modeled and the models tested.

ID has a predetermined endpoint, but no model or theory to account for it, no falsifiability (and thus no data), and no science. It does have lots of dishonesty, willful ignorance and stupidity, arrogance, and ambition to power, but not much else (including the faith that is allegedly its motivation).

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12. Alig on February 3, 2009 1:33 PM writes...

ID and evolution are both proven to occur. Unless you are saying that Round-up Ready corn, Golden rice and Green-fluorecent bunnies evolved?

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13. Jose on February 3, 2009 2:17 PM writes...

Proven to occur via His Noodly Appendage!

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14. Cellbio on February 3, 2009 2:44 PM writes...

Hey Jose! At last, a Pastafarian!

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15. RB Woodweird on February 3, 2009 3:22 PM writes...

MedChem,

You are starting with a conclusion and making the data fit to it.

Try that at work and see how far you go.

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16. Dana H. on February 3, 2009 3:24 PM writes...

Alig: excellent point. The only rational use of the term "intelligent design" is to refer to the achievements of human ingenuity -- not just in biology, but everywhere (e.g., the iPod).

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17. Sili on February 3, 2009 3:37 PM writes...

I need to start reading Chem World again. I've fallen out of the habit of even looking at the crossword while I've been sick. Glad to see you're still writing for them (do you get free membership of the RSC in turn?).

I think dr Behe has amply illustrated that there is indeed an intelligent designer. And more importantly that his favoured creation is P. falciparum. All the rest is incidental.

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18. C. Bailey on February 3, 2009 3:53 PM writes...

One thing I'd like to see more of is mixing biosynthesis with conventional synthetic methods. I know that using enzymes as a reagent has been kind of sort of worked on since the '70s, but we have much much better bioinformatic tools to keep track of what gene goes with what enzyme. Why can we use a bacterium to make a polyketide (that would take a bajillion steps to make synthetically) and then use synthetic chemistry to derivativitize it to make it better for whatever purpose we want it for? Or messing around with ordering modular biosynthetic genes (such as PKS genes) in a way that requires retrosynthetic analysis not unlike conventional total synthesis? Or using biosynthetic genes from bacteria to make pieces to glue together with traditional synthetic methods?

There just seems to be so much potential in working with nature now that we have much much better analytical tools for structure determination and purification and huge databases of bioinformatic information and BLAST alligns and such. I only see this being tapped a little bit in the chemical biology lit, but it seems like a way to make total synthesis way more efficient. I guess it just requires that someone be a synthetic organic chemist, enzymologist, and geneticist at the same time.

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19. MedChem on February 3, 2009 3:55 PM writes...

RB:

"You are starting with a conclusion and making the data fit to it."

Think about it, you're not? I look at this the same way I look at multiple scientific theories trying to explain the same observations--which one makes the most sense of the observations. To me, evolution simply doesn't make sense.

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20. anon on February 3, 2009 4:02 PM writes...

The way I see it is both mechanisms should thought of as theories. One that is faith based and inheritently cannot be proven (belief mandiating proof is not faith). And one that is fact/science based and has yet to be fully proven (mostly due to our lackluster understainding of the biochemistry of living systems - especially as translated onto macro evolution) and transformed into scientific law. Thus, choose which theory fits best into your world view and advance the hell outta it.

In more direct response to the post: how then can we harness what mother nature has so kindly engineered for us. Would time and dollars be better spent coming up with ways to use enzymatic processes in useful synthetic ways? Now that we can pretty much "make anything" via brute force should we consider putting reources into more elegant, possibly enzymatic routes, in mainstram synthetic groups. Or should we leave this to the bioinorganic types?

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21. S Silverstein on February 3, 2009 6:53 PM writes...

This is an elegant and brilliant post. Thanks.

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22. RB Woodweird on February 3, 2009 8:18 PM writes...

MedChem,

You have been indoctrinated into the currently popular superstition, that's all. If you had been born in the past, you would have thought the same about Zeus or Zoroaster as you do about Jehovah - with equally as much proof.

What conclusions am I starting from? I have human biases, but I am willing to toss out anything I think I know if evidence is offered. You are not.

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23. SRC on February 3, 2009 11:53 PM writes...

Pet peeve: "Compounds," not "molecules." Proper use is in the sentence, "molecules of the compound cyclohexane adopt a chair conformation." "Compound" refers to the class, "molecule" to the individual member of that class. It's akin to saying we have a soldier in Iraq.

Anyone who synthesizes a "molecule" literally has a very low yield indeed, and is wasting his time.

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24. Jim Hu on February 4, 2009 12:07 AM writes...

The selection part matters, medchem.

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25. processchemist on February 4, 2009 4:50 AM writes...

uhm... about phenomena that can be modelled but not explained, obviously no medicinal chemist has ever used DOE to optimize a crystallization... soft models have something to do with the limits of the human mind in describing mathematically complex systems.

ID whas one of the issues of Kant's "trascendental dialectics", and speaking about that, we all talk about atoms, electrons and so on, but no one has ever seen one of such objects, only something that we call their "experimental evidence" (their effects).
What's producing phenomena (philosophically) is out of reach for experimental sciences, and IMHO all we (as scientists) can say about it is that we can't say anything at all.

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26. Nick K on February 4, 2009 7:58 AM writes...

Thank you, SRC. Similarly, it is absurd for Pharma companies to boast about the number of "molecules" they have in development. Either that or their drugs are incredibly potent.

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27. MedChem on February 4, 2009 11:00 AM writes...

Even when I was an agnostic, I knew deep down that the inorganic-to-organic-to-human evolution was a bunch of nonsense. I believe even an ardent evolutionist, if he's honest with himself and searches deep enough in his heart, feels the uneasiness, unless one is so incredibaly intellectually arrogant as to think he's got most things figured out. As scientists, especially in biology and chemistry, we should know that's nowhere near reality.

I'm speaking in general terms and mean no insults.

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28. MTK on February 4, 2009 1:04 PM writes...

Medchem,

You know what's also "intellectually arrogant"?

To believe that there is an all-knowing, all-powerful being that created all things and that out of all the life forms that being created that one, and only one, was created in his image and that that one is you. Now that's arrogant!

I speak only generally and mean no insult.

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29. Hap on February 4, 2009 1:17 PM writes...

I would sort of figure it's more arrogant to assume you know what you don't. Evolution works because it asks questions whose answers can be observed and independently verified by others - it doesn't claim to know if there's a God or not, because that isn't a question data can answer. ID doesn't bother to ask an answerable question - how do you prove that something can't happen? - and doesn't even suggest anything valid to ask. If you can't ask a reasonable question, you can't get a reasonable answer.

Evolution fits data from a variety of sources (not just biology), like an answer in a crossword which has to fit all of the intersecting answers. If it doesn't fit the intersecting words, then it has to be changed, or deleted. ID doesn't even seem to think there is a puzzle. It substitutes a (IMO, bad) interpretation of the Bible for actual data, so even if put forth honestly, it really doesn't allow one to do anything useful. Since there are at least two Eve creation stories in Genesis, a literal interpretation of the Bible (the motive for ID/creationism/whatever it'll be called next) isn't even internally consistent.

Whether observable reality is all there is is an open question (which we can't answer, anyway), so presupposing some other way of knowing would require evidence - explanation of something in the physical realm that can't be explained at all, otherwise, for example. Science works because we can independently observe lots of things that other people have seen - it doesn't depend on things that could be going on solely in my head and nowhere else or which can't be shown to do so by others. It doesn't say they don't exist - just that it's not its bailiwick.

Also, "evolutionists" doesn't really help. People don't believe in evolution - it simply fits the data. If something else does so better, it (after some hemming and hawing) will be accepted. ID doesn't have anything that could disprove it - based on the honesty of many of its proponents, data is something to which it has a severe allergy. Something you can't question and which nothing observable can affect is dead in an intellectual sense (and probably in amoral and religious sense, as well) and is not useful for anything constructive.

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30. RB Woodweird on February 4, 2009 2:32 PM writes...

I end this discussion with the words of Samuel Clemens:

"Faith is believing what you know ain't so."

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31. JK on February 4, 2009 7:09 PM writes...

There's some move toward using bacteria for biofuel synthesis. The problem there is different to medchem: making simple compounds such as butanol and short branched alcohols on very large scales. A fair bit of the work seems to be on tweaking the metabolism so that most of the bacterial effort goes into making the desired product (addressing MTK's first two concerns right at the beginning of the thread). I guess that with the potential market and scale of biofuel synthesis it's worth the effort putting together the bacteria. Maybe if the work is pioneered with these simple systems it will be a step toward being able to design and build bacteria for more complex chemical problems?

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32. DC on February 5, 2009 12:07 AM writes...

To 28-30:

I would totally agree with you guys if I believed in the dogma of scientific naturalism.

But I don't - and here's some of the reasons why.

Do you love your mother? Of course. Can you prove it scientifically? There are things we value in life that cannot be measured by the yardstick of science - but does that mean they do not exist?

That's like saying, I can't see microwaves, so they don't exist. Perhaps we need to look at it from another avenue?

Religion is unscientific because there is no (scientific) evidence for it / it cannot be proven (scientifically). Circular reference?

When your definition of reality is all that can be proved by science, that is scientific naturalism, and it is a belief, a worldview, just like any other. Can you prove that it is the correct worldview?

Obviously, no one can prove that their worldview is correct, and that others are wrong. However, we can look at the data and see which conclusion fits it best. Let me put aside guessing and tell you that I come from a Christian worldview.

Here's the crunch - the way we look at data is inherently based on our own worldview. If we believe in scientific naturalism, then we would naturally exclude all supernatural phenomena (e.g. resurrection) because they simple "can't happen". What if it did happen? Well, it couldn't, it's impossible, there must have been a mistake. This is closed-minded thinking. In fact there is much historical evidence that a person named Jesus died, and that his resurrection was witnessed by many. So it seems to me that a much more important point of contention should be whether or not the evidence for Jesus' resurrection is sound, and not whether or not it is possible in the first place.

RB and others seem to believe that faith excludes reason. They are mutually contradictory. That faith is believe in the absence of reason, or even in spite of reason.

But think about it: when you tell your underling "I have faith/believe that you will be able to do this reaction". Do you say that because you have done some kind of futuristic scientific experiment that proves that he is capable of it? Or is it because of your past observations/trust in him? There are some things that we are unable to prove, but because of certain reasons, we can say that we have "faith" in it.

In the same way, Christian faith is not blind, it is based on good reasons, some scientific, some historical, some philosophical, and even divine relevation. But I'll save those for the next post :)

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33. Hap on February 5, 2009 3:18 PM writes...

I think you're forgetting about this pesky thing called data. I don't need to see microwaves to know they exist - there are other ways to determine that. The difference between scientific evidence and other types of evidence is that I don't already have to believe in data for it to exist. Others don't see religious experiences independently - how can I tell what I experience exists somewhere other than just inside my own head? (The closest we have to such is testimony, which is hard to validate, particularly long after the fact, and can be made to look silly even for events occurring in the very recent past.)

Evolution (or science) doesn't require that I not believe in God or anything else - it can't disprove them, so it doesn't bother. ("Whereof I do not know, I must remain silent.") If you want to claim a divine origin for life, one not compatible with evolution, you are making a testable claim or two [1) evolution isn't true and 2) I have a better model]. If you have no data to support that claim, then your claim is not valid (you can only validate it with observable data). If you want to play in a scientific arena, you play its rules or not at all.

I don't have to believe that observable reality is all - but whatever beliefs I have external to it must deal with its existence. I can hope that things can different than they are, but in order to interact with the world and possibly to change it, I have to deal with what is. Observable data may not be all, but it is an unignorable piece of the puzzle, and if one's faith forces one to ignore it, there may be a problem.

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34. anon on February 5, 2009 3:25 PM writes...

#32:
"In fact there is much historical evidence that a person named Jesus died, and that his resurrection was witnessed by many. "

I think you should do a bit more research on this topic. (without relying on texts that were countlessly revised throughout the centuries). I mean actual research, not google. You'd be surprised by how little to no historical record there is that Jesus actually existed during his time. Most "accounts" of him came centuries later.

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35. DC on February 5, 2009 7:15 PM writes...

#33-34 Thanks for your reasoned replies.

#33: I agree mostly with you, let me think of a reply...

#34: That would be a very important issue to the Christian faith, and while I have my views and opinions I'm in no way an expert, so I'll let the scholars (on both sides) have their say...

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36. Anonymous on February 5, 2009 9:50 PM writes...

#34 said "You'd be surprised by how little to no historical record there is that Jesus actually existed during his time. Most "accounts" of him came centuries later."

You are telling people to get their facts straight, but your statement that no accounts of Jesus were written until "centuries" later sounds like you are deliberately trying to mislead people (or you just haven't done any research yourself). Regardless of their point of view about the historicity of the narrative, most scholars would say that the gospels were written no later than mid- to late-second century (many would say much earlier). They were *not* subsequently revised for centuries.

You can make good, rational arguments for not believing the gospels, but you should do so from the facts, not by distorting the facts in an attempt to belittle your opponents. I apologize for continuing to take things off-topic, but, as most of us are scientists, we should understand the importance of being precise about what we say.

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37. Anomuumi on February 7, 2009 8:18 PM writes...

On a tangent: don't you notice - I can't help to notice - that the Creationists (big C, like in Communism), when manufacturing a controversy, tend to use personal and emotional words a lot. Like, "nonsense", "ardent", "when I was", "makes no sense", etc. It becomes jarring after reading the first reply.

The fact is that we, as scientists, cannot counter their arguments. This is because they speak in emotional language, and seek "emotionally optimal" answers, not factually correct or analytical answers. Our answers can never "feel good" to them, because they don't conform to their worldview. Furthermore, it is impossible to un-indoctrinate someone; people can't change. Options are few; either write the analytical response and hope that someone else reads it and is convinced; or something more difficult, try to elaborate one's own emotional reasons for accepting scientific theories.

As for the topic, the biggest problem with natural reactions is their specificity. I think that most of the very efficient (primary metabolism) enzymes would take impossibly long to develop in a lab, even if we knew how. Do you agree? There are only so many reagents you want to try, especially if you want a quick-and-dirty reaction; the same would apply here.

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38. Man Singh on January 9, 2010 4:37 AM writes...

Initiation of thought process is appreciable as it triggers variety of opinions and views on specific dent. Probably it takes forwards the scatterd opinions to converge in a form of thesis.

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