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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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August 6, 2010

Organic Chemistry: A Lack of Challenges?

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Posted by Derek

I had an interesting email in response to my post on returning from the SciFoo meeting. I have to say, there weren't too many chemists at that one - not that it's a representative slice of science, to be sure. (Theoretical physicists and computer science people were definitely over-represented, although they were fun to talk to).

But perhaps there's another reason? I'll let my correspondent take it from here:

I worry a lot about organic chemistry, about the state of the discipline. I worry about the relative lack of grand challenges, and that most academic work is highly incremental and, worse, almost entirely the result of screening rather than design. There is still so little predictive power (at least in academia) in drug or catalyst discovery. I have a theory that the reason we're so brutal with each other in paper and grant refereeing is because we're essentially dogs under the table fighting for scraps.

There are big exceptions, which make me excited to be a scientist. There's usually something in Nature Chemistry that has the wow factor, for example. They're just so rare. . .

He went on to point out that other fields have results that can wow a general audience more easily, which can make it harder for even excellent work in chemistry to get as high a profile. As for that point, there may be something to it. High-energy physics and cosmology would, you'd think, be abstract enough to drive away the crowds, but they touch on such near-theological questions that interest remains high. (Why do you think that the press persists in calling the Higgs boson the "God particle"?) And biology, for its part, always can call on the familiarity of everyone with living creatures, possible relevance to medical advances, and the sheer fame of DNA. All these fields have lower-profile areas, or ones that are harder to explain, but they always have the big marquee topics to bring in the crowds.

Chemistry's big period for that sort of thing was. . .well, quite a while ago. We're at one remove from both the Big Overarching Questions at the physics end and the Medical Breakthroughs at the biology end, so our big results tend to get noticed according to how they relate to something else. If (for example) chemists achieved some breakthrough in artificial photosynthesis, it would probably be seen by the public as either physics or biology, depending on the inorganic/organic proportions involved.

But what about the first point: are we really running out of big questions to answer in this field? It's easy to think so (and sometimes I do myself), but I'm not so sure. Off the top of my head, I can think of several gigantic advances that chemistry could help to deliver (and hasn't yet). Room-temperature organic superconductors. That artificial photosynthesis I mentioned, to turn the world's excess carbon dioxide into organic feedstocks. Industrial spider-silk production. Small molecules to slow the aging process. A cheap way to lay down diamond layers on surfaces. And I haven't even mentioned the whole nanotechnology field, which is going to have to depend on plenty of chemistry if it's ever to work at all.

Now, it's true that looking through a typical chemistry journal, you will not necessarily find much on any of these topics, or much to make your pulse race at all. But that's true in the journals in even the most exciting fields. Most stuff is incremental, even when it's worthwhile, and not all of it is even that. And it's also true that of the big chemistry challenges out there, that not all of them are going to need organic synthesis to solve them. But many will, and we should be encouraging the people who feel up to taking them on to do so. Not all of them do. . .

Comments (56) + TrackBacks (0) | Category: Chemical News | Who Discovers and Why


COMMENTS

1. Wavefunction on August 6, 2010 9:19 AM writes...

I tend to think of chemistry as the lights, set and sound behind the show. Not as prominent as the actors but an essential and integrated backdrop without which the show could not exist.

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2. Tok on August 6, 2010 9:20 AM writes...

As far as general press is concerned, chemists also have to deal with the layman's use of the word "chemical" to mean something almost universally considered "bad". There isn't much of that in physics, cosmology, or biology.

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3. AlchemistOrganique on August 6, 2010 9:44 AM writes...

Perhaps chemistry is too practical and mundane to have the razzle-dazzle of esoteric studies such as cosmology or impractical biology. It's great transgenic model organisms can be engineered to fit studies worthy of publication in PNAS and Science. However, we are not going to make transgenic people. Venter's promises of personalized medicine have yet to be met, even though we are asymptotically getting closer.
@ Wavefunction: To me chemistry is like the dough of pizza. It is versatile and provides support to the showcase toppings. Yet in the end the under-appreciated crusts are tossed out with the rest of the trash.

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4. silicon scientist on August 6, 2010 10:21 AM writes...

Many of the "grand challenges" you mention are being pursued under the banner of "materials science." If you broaden your view to include the worlds of polymers, organic semiconductors, etc., then organic chemistry is quite a lively place at the moment.

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5. processchemist on August 6, 2010 10:42 AM writes...

IMHO there's still plenty of room for improvement. If we think about how good are living beings in assemble molecules of great complexity, our chemical synthetic abilities are, in the best case, sloppy.
The problem is maybe that we require a prigoninic jump in the whole field of catalyst/ligands research, based on some different approach still to be devised.

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6. heteromeles on August 6, 2010 10:43 AM writes...

Hmmm. I'm not a chemist, just an ecologist who's no longer looking for a job in academia (talking about brutal funding cuts, ahem, guys: your biology envy is radically misplaced).

I honestly disliked general chemistry (I have little talent for it) and I was forced to take non-majors organic chemistry for my PhD. I liked that class just fine, but as a requirement for my PhD, it was stupid: what on earth do I need to know about high temperature reactions with organic solvents? My world is aqueous reactions in aqueous solvents, and I didn't see anything on that until the last day of class, when we talked about DNA. To this day, I've used almost nothing from that class, and while it was informative, it was objectively a waste of time.

So, speaking as a foreigner, I'd say that's the challenge for organic chemistry: room-temperature reactions in water, preferably with stuff that can be readily broken down if it gets spilled.

In fact, I'll wrap that plea around a big, oil-soaked pelican corpse from the Gulf and throw it through one of your plate glass lab windows, if that would help.

I mean, we know fossil fuels are running out and we're going to be facing an energy crisis. Where's the R&D on the replacement processes for all the organic products we won't be able to make at a large scale in 50 years?

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7. Dr. smalls on August 6, 2010 10:43 AM writes...

The grand challenges in chemistry (things with WOW factors) are more applied now rather than fundamental. Most people don't care about the total synthesis of whocaresotoxin via unprecedented chemical reactions, but if the product tosses breast cancer into remission (regardless if the molecule can be produced industrially) in rats, then people take notice.

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8. Fries With That? on August 6, 2010 10:45 AM writes...

Why does high throughput screening continue to be the ugly duckling of drug discovery? It gets so little respect, it's so disparaged, yet time and time again, the results from HTS produce drug hits which turn into leads which turn into products. Yes, there is an element of luck to it, yes, oftentimes it does not work at all,but the scientists who take the information and run with it are performing science just like anyone else. Also, the importance of setting up the screen and not choosing artifacts as hits comes from biologists and chemists working together to recognize such occurrences.
Sigh.

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9. retread on August 6, 2010 10:50 AM writes...

The hell with utility. For me (but not for people who have to make a living and support their families) organic chemistry is an esthetic pursuit, just like music. For one example, look at the current edition of Clayden p. 949 (synthesis of citral). Some very elegant organic chemistry occurs in the body and is crucially important to our survival. Check out p. 956 -- synthesis of vitamin D2 from ergosterol which uses an electrocyclic reaction followed by a [1,7] sigmatropic shift.

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10. CMCguy on August 6, 2010 11:06 AM writes...

Like many things Org Syn may have reached a state of maturity that the class of grand challenges have gotten bigger so harder to achieve from perspective of past efforts but there is room to diversify. Excellent analogy by #1 Wavefunction as chemistry often makes contributions that enable practical applications in science and #5 processchemist is correct in that the contributions could be done even better. Unfortunately as #2 Tok suggests chemistry often viewed with negative connotations. May be beyond the grand challenge stage yet as often bemoaned here without some significant progress in discovering and development of new drugs (small molecules in particular) some of the most direct evidence that could be offered is dormant.

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11. bbooooooya on August 6, 2010 11:27 AM writes...

"organic chemistry is an esthetic pursuit, just like music"

Roald Hoffman said something along those lines in the 80s. I don't think it's true anymore. I think it's now more mechanics.

I doubt most of the pretty stuff KCN does has much utility: the nuts and bolts, sure, but what he (and others) have done is to reduce organic synthesis from art to engineering; they've proven that (with enough foreign PDFs who fear for their J-1s) if you can find a molecule in Nature, you can make it. Big whoop. And pass the salt.

it is gratifying when a chemist finds a molecule that ends up helping cancer patients. In the end, the chemist will get 0 credit, and will be lucky to still have a job.

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12. formerlawyer on August 6, 2010 12:15 PM writes...

My father, a retired Professor Emeritus of Physical Chemistry, would concur with siliconscientist - the action and the most game-changing developments would be in the material sciences. Quantum computing, organic substrates, nanomachines, new low-lubricant surfaces, more durable coatings etc. etc.

Given the coming energy and environmental challenges - this may not be too soon.

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13. Notmedchem on August 6, 2010 12:16 PM writes...

I read this article earlier today:

http://www.mindfully.org/Industry/Reign-Of-Chemistry-5jan53.htm

and it's highlights the points. Chemistry, Big Chemistry was first. We're the granddaddy of the applied sciences. We don't have any more big questions, but what we do is central to pretty much everyone else, except maybe astrophysics.

Organic Chemistry is about making molecules. I know most focus on drugs, but functional materials made of molecules are where organic chemistry has taken us.

It's a big continuum: The synthetic methods/natural products gives us the tools for the synthesis, macromolecules, supramolecule folks to make things with interesting properties, which gets picked up the materials scientists/engineers to make specialty and fine chemicals/materials.

Organic Chemistry isn't all about drugs...hence blogs like CBC.

@6 there are folks working on new feedstock molecules mostly esters/acids, it's the aromatics and partial aromatics that don't seem to have good "sustainable" starting points.

As for RT reactions in water, I always thought that's what biochemists did with the help of those weird things called enzymes...

Polarity is only for transition states, man.

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14. retread on August 6, 2010 12:44 PM writes...

#11 -"organic chemistry is an esthetic pursuit, just like music"

"Roald Hoffman said something along those lines in the 80s. I don't think it's true anymore. I think it's now more mechanics."

I knew him back in '62 and can see him saying something like that. The reason I go by the name Retread, is because that's exactly what I am.

I'm in the process of catching up on the organic chemistry of the last 48 years purely for esthetic reasons. I doubt we know all there is to know about organic chemistry presently. Clayden is very skimpy on how various metals interact with carbon. Even the topic of my junior paper written in 1958 -- the structure of the Grignard reagent doesn't appear to have been settled.

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15. chris on August 6, 2010 12:46 PM writes...

The total synthesis of a virus by Craig Venter caused quite a stir.
I'm always irritated when I see headlines suggesting "Doctors find a cure...." when in fact they merely diagnose and prescribe, it is the chemists who design and create the molecule that becomes the drug.

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16. Aspirin on August 6, 2010 1:02 PM writes...

"organic chemistry is an esthetic pursuit, just like music"

That may be true for you and it was certainly true for people like Woodward fifty years ago, but I don't think that's largely the case anymore. Most of the top organic chemists today are worried about other things (efficiency, 'green' chemistry etc.) and not aesthetic beauty. Shooting for the synthesis of maitotoxin with 20 postdocs in a cutthroat contest and hammer and tong approach is hardly anyone's idea of beauty. In other areas like materials synthesis and bio organic chemistry, organic chemistry has been pretty much reduced to an important but utility-providing science. Phil Baran may be one of the few chemists around who still appreciates the aesthetic motivation for synthesis.

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17. Anonymous on August 6, 2010 1:15 PM writes...

In 1967 one prominent chemist decided that chemistry had all been done and took himslef off to work in Artificial Intelligence.
http://en.wikipedia.org/wiki/H._Christopher_Longuet-Higgins

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18. psi*psi on August 6, 2010 1:32 PM writes...

Room-temperature organic superconductors. That artificial photosynthesis I mentioned, to turn the world's excess carbon dioxide into organic feedstocks. Industrial spider-silk production. Small molecules to slow the aging process. A cheap way to lay down diamond layers on surfaces. And I haven't even mentioned the whole nanotechnology field, which is going to have to depend on plenty of chemistry if it's ever to work at all.

Funny how most of these challenges you've mentioned fall neatly within the realm of organic materials. And we really could use some people with good synthetic skills. If we could add some complexity to some of our targets without sacrificing too much yield, we might be able to do some amazing things.

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19. milkshake on August 6, 2010 1:38 PM writes...

most stuff in org chemistry is not incremental - right now it is rather excremental if you want to make living from it.

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20. milkshake on August 6, 2010 1:41 PM writes...

material science: it is strange how many properties kinase inhibitors share with organic materials for photovoltaics: flat polycyclic structures, terrible solubility, funny colors

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21. ronathan richardson on August 6, 2010 2:01 PM writes...

How about orally bioavailable small molecules that specifically inhibit a transcription factor.

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22. Mat Todd on August 6, 2010 2:40 PM writes...

Artificial photosynthesis is a nice example for this discussion. Very important area, big science, wow. But the design of the molecules required (and their mutual arrangement in space) is physical chemistry, or even straight physics. Making the relevant molecules will most likely be easy. While org chem is involved, I'd say we're a service industry there - "the lights, set and sound behind the show" (#1)

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23. J. Peterson on August 6, 2010 2:52 PM writes...

Semi-related cartoon.

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24. Chemjobber on August 6, 2010 3:28 PM writes...

It is really worth pointing out that the Bureau of Labor Statistics says that growth in material scientist positions is supposed to be 12% between 2008 and 2018; by contrast, BLS suggests only 3% growth for chemists. (Granted, from an absolute point of view, there are 10X more chemists.) So, organic materials is probably a good place to really start thinking about jobs.

If I had a nickel for every company that's been begging for PhDs for battery research on the ACS Careers database, I'd have a lot of nickels. That being said, it's not enough to soak up the affected in pharma's recession.

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25. BlueBaron on August 6, 2010 4:47 PM writes...

It's more a problem of the nature of chemistry. We know what we can do, and we can take a structure and probably make it. The real questions are, what do we make? Engineering such molecules is still infinitely harder than putting a man on the moon. There, there are proven methods to predict and derive the optimum conditions to achieve the goal. None such exist to optimize binding and pharmacology based on "discoveries" in the "laws" of chemistry (without some incredible advances in math, physics, and computers). Compound that problem with the complexities of organisms and ecosystems, yikes.

A lot of synthetic chemistry operations are like mechanical operations and brute force experimentation. It's about 10% figuring out what to do and analysis and 90% hands-on running the experiments. It should then come as no surprise that chemistry jobs are being shipped in the same direction as US skilled factory labor.

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26. TFox on August 6, 2010 5:03 PM writes...

Note that the DOE recently held a $122M competition for a general sunlight-to-fuels program. They gave the money to a chemist: http://bit.ly/aMFYFB.

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27. Industrialist on August 6, 2010 5:45 PM writes...

# 6 "Where's the R&D on the replacement processes for all the organic products we won't be able to make at a large scale in 50 years?"

Generally in the R&D functions of the companies who make them already - oil and gas and petrochemicals.

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28. Curt F. on August 6, 2010 6:06 PM writes...

Let me see if I can paraphrase the gist of the various commenters here:

1. Chemistry used to be a largely fundamental scientific endeavor, that is it used to be a mainly about a search for truth and knowledge. Before Kekule and Dalton, before the periodic table, and before atomic physics, man did not know what things were made of, but could only guess. Now, continuing to paraphrase Poul Anderson, we have a theory of matter and energy that observation bears out, both in the laboratory and in our daily life.

2. Since we have a theory of matter and have developed robust methods to exploit the nature of matter to our own ends, the "pursuit of truth" angle to chemistry has been diminishing for some time: There really aren't any more great unknowns in chemistry.

3. Chemists now apply their art in fields like physics or biology. There, they are unseen "service providers", like the set, the lights, and the sound behind the actors on a stage.

---
In other words, chemistry is changing from a scientific endeavor to a technical one. Chemists of the world, we are all engineers now.

John Prausnitz saod, "If engineering is the application of science for human
benefit, then the engineer must be a student not only of the application of science, but of human benefit as well."

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29. Mat Todd on August 6, 2010 6:40 PM writes...

#28 - I think the original discussion was specifically about organic chemistry, not chemistry more generally.

#26 - that team you linked to which won the sunlight-to-fuels program is led by a chemist, but he's not an organic chemist by any stretch. "Research in the [Nathan] Lewis Group focuses on applications of electrochemistry and photoelectrochemistry to present-day issues in energy and chemical sensing"

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30. Dirk on August 6, 2010 11:52 PM writes...

# 6 "Where's the R&D on the replacement processes for all the organic products we won't be able to make at a large scale in 50 years?"

# 27 "Generally in the R&D functions of the companies who make them already - oil and gas and petrochemicals."

And in VC-funded start-up companies. I work for one of them.

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31. barry on August 7, 2010 6:07 PM writes...

On the Nobel-prize level, I can't point to a problem/solution in Organic Chemistry that has risen to the level of Woodward's B12 synthesis in some decades. There are however real problems remaining. E.g. Real small-molecule modulators of protein-protein interactions (especially mammalian transcription factors) could really push the horizons of what is treatable pharmaceutically.

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32. Anonymous on August 7, 2010 6:31 PM writes...

HG Wells' "Food of the Gods" describes a country village terrorized by giant wasps. The village government send to Oxford for a team of scientists, who come out and study the wasps for several months while the villagers hide indoors. Frustrated, the mayor contacts the Royal College of Engineers, which sends out a team with torches and burns out the nests.

Nothing wrong with being an incrementalist or doing applied science.

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33. Got _QSAR? on August 7, 2010 9:58 PM writes...

"There is still so little predictive power (at least in academia) in drug or catalyst discovery."

In my opinion the next major break through in drug discovery is going to be the improvement/perfection of the "predictive power".

Scoring functions and docking algorithms will continue to improve both in speed and accuracy as time goes on. There is definitely need for improvement and I hope that I get to see it "perfected" in my lifetime. The 'holy-grail' of drug discovery being (predicted deltaG)/(experimental delta G) = 1.

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34. fungus on August 8, 2010 1:00 AM writes...

Nature can do point oxidations on aromatics, seemingly at will. That's a big deal. Imagine taking an indole and making 6-hydroxyindole without resorting to protecting group shenanigans or making it from precursors. There's two important things there - 1) doing the oxidation in the first place without touching the 5-membered ring of the indole, and 2) overriding the aryl ring's natural tendency to go for the 5-position.
Electrophilic aromatic substitution may sound boring, but it's still something nature knows how to do better than we can.

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35. Jose on August 8, 2010 4:03 AM writes...

'In my opinion the next major break through in drug discovery is going to be the improvement/perfection of the "predictive power".'

We've been hearing this for 15+ years. Check out the JMedChem from 2-3 yrs (OK, 5 years) ago where the modeling group at GSK with unlimited time and package options couldn't make the models find known crystal structures.... "A Critical Assessment of Docking Programs and Scoring Functions."

(Derek had a post on Nov 1 2005....)
I am pretty certain things have not changed in 5 yrs, nor will they in another.

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36. Sebastian on August 8, 2010 7:14 AM writes...

Funny. Sitting at my uni desk thinking to myself, "okay, so this PhD project means something, but GOSH I am so bored by it." There's no fringe thinking in it, and this boredom led me to open up ITP for a quick read - lo and behold, in all its ironic glory, a post about the same thing.

I was actually going to post on here if anyone had any interesting ideas for me to toy with (however chemistry is such a huge field that one cannot simply answer that question).

I've got some cool ideas for chemistry, all fringe, however as many can attend, finances usually only permit very basic projects with near-guaranteed success rates.

I'm not sure where chemistry is heading, but it sure is boring at the moment, with screening-based discovery methods.

Curt F. has it right on the money, we are engineers now, not scientists.

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37. Sebastian on August 8, 2010 7:25 AM writes...

Just a quick addition - sorry for the double post.

I remember seeing a video recently which basically describes issues with innovation and discovery which I believe is relevant. Basically, the people with the "big problems" are usually bigwig CEO's and project managers with lots of money. Since they are accustomed to spending lots of money, they subconsciously believe that "big problems are fixed with lots of money". Unfortunately innovation and finance are often not a linear trend - not only can large sums of money actually hinder innovation, but it is a waste.

Some of the best inventions and innovations came out of people's garages. They had an idea, a way to do something with what they had - usually with little to no money.

I think researchers in large institutions are starting to 'retrain' their brains into this unfortunate way of thinking. We don't need more papers, we don't need more money - there's an excess of this already available. Chemistry needs some sort of forum that allows people to discuss innovation, free from patent and financial pressure. We need to induce a paradigm shift from lots-of-money + same-old-boring-science = "progress" into something along the lines of forget-about-the-money + extravagant-ideas = progress. IMHO, of course.

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38. Bubba on August 8, 2010 11:23 AM writes...

The seeds for the slow demise of organic chemistry were sown long ago. Instead of synthesizing the natural product strychnine used "for the etermination of rodents and other undesireables" Woodward and coworkers may have served the future direction of organic chemistry better by solving the strucure of DNA.

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39. Anonymous on August 8, 2010 1:57 PM writes...

"I am pretty certain things have not changed in 5 yrs, nor will they in another."

Jose, I envy your "predictive power". Rim Shot

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40. Got_QSAR? on August 8, 2010 2:04 PM writes...

The above post #40 was mine. The 'Anonymous' was not intentional.

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41. Paul D. on August 8, 2010 4:19 PM writes...

I'm wondering if you saw this:

http://www.eurekalert.org/pub_releases/2010-07/tkai-nss072710.php

Native-like spider silk produced in metabolically engineered bacterium

"[...] To study the mechanical properties of the artificial spider silk, the researchers determined tenacity, elongation, and Young's modulus, the three critical mechanical parameters that represent a fiber's strength, extensibility, and stiffness. Importantly, the artificial fiber displayed the tenacity, elongation, and Young's modulus of 508 MPa, 15%, and 21 GPa, respectively, which are comparable to those of the native spider silk. [...]"

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42. dvizard on August 8, 2010 7:18 PM writes...

"Room-temperature organic superconductors. That artificial photosynthesis I mentioned, to turn the world's excess carbon dioxide into organic feedstocks. Industrial spider-silk production."

Yeah, that would be great. BUT everyone in academic OChem seems to prefer working on synthesis of insanely complex natural products. Until not too long ago, polymer chemistry was looked down upon as "not-really-chemistry" and is getting more respect now as material sciences get bigger, but is still not seen as organic chemistry by organic chemists. So who is surprised about OChem not making the big news?

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43. Seth Goldberg on August 9, 2010 2:06 AM writes...

As a complete outsider, I was always very disappointed and confused by the way that chemists apparently were not able to describe to the generally scientifically educated reader why the hard problems were different from the easy ones except in size.

The theory didn't shine through for me. The vocabulary was either too general or too specific, and so the field appeared as all application, not a bad thing but somehow limited. A counter example of synthetic chemistry which did seem interesting was Orgel's experiments on origin of life, or Cairn's Smith's modifications, etc., maybe because the results were anti intuitive with respect to my naive expectation of rates. In ordinary chemistry, as an educated layman, I have no naive intuition of rates or much else to be challenged, so there is little room for a dramatic story.

Biochemistry seems interesting in detail, especially as structure keeps on revealing the basis of function.

In summary, what low level review articles on any subfield can you recommend that will quickly teach me enough to be amazed at exceptions to theory, and then satisfyingly explain why?

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44. schinderhannes on August 9, 2010 5:13 AM writes...

Man sometimes it is great to live in Germany:

"Why do you think that the press persists in calling the Higgs boson the "God particle"?"

Never ever heard that one!
We are just a little bit less obsessed with religion over here.

ROTFLH

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45. Anonymous on August 9, 2010 5:48 AM writes...

It's amusing that so many here think that organic chemistry is in any way a mature science, when so much of the lit is full of hackneyed 50+ step routes to big natural products in minuscule amounts. We CAN make anything, but NOT with acceptable efficiencies. What we need is more practical science and a good start would be refusing grant applications for natural product syntheses where the goal is to make anything less than gramme quantities of the final compound. Maybe JACS and JOC could refuse to publish papers on syntheses where the authors fail to make a decent quantity at the end. At the moment there is far too much bollockomycin synthesis research that gets funding that it doesn't deserve. Organic chemistry will only regain its status when it chooses to shoot for the bigger problems.

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46. Sebastian on August 9, 2010 5:59 AM writes...

#45 I have to disagree.

For 99% of papers, efficiency is not the target, a particular product in suitable quantity for charactarisation be it spectroscopically, biologically, etc, is the target.

If the target is made in enough quantity to be used for validation, it is usually up to industry to optimise parameters for cost efficient production. Research chemistry, gram per gram, is hideously inefficient, because it's not a care factor in publishing papers.

(unless of course the paper is about increased reaction efficiencies and sometimes in total-synthesis papers).

Those big arse natural products, if can be charactarised and show excellent promise, are often then subject to biological manipulation of the host (plant, organism, etc) in order to express larger amounts of that particular molecule, or precursors so that at least nature has done most of the work.

A good example of this would be the artemesinin family of compounds. Subject to isolation of an active molecule from artemesia plants, and subsequent successful biological charactarisation, researchers are now modifying the host plant to produce more of the target or precursors so that it can be viable on a commercial scale.

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47. Wavefunction on August 9, 2010 7:33 AM writes...

-A Critical Assessment of Docking Programs and Scoring Functions (2004)

35: Since then other deficiencies in docking programs have been identified (such as the absence of explicit waters) and these are being remedied. The programs have become much better since 2004 at finding the crystal structure. The real problem is calculating the free energy. We are a long way off but we are inching forward.

45: Organic chemistry will only regain its status when it chooses to shoot for the bigger problems

Sure, but the problem is that these "bigger problems" may not be in the realm of classic organic synthesis, although synthesis will still provide very important inputs (but again, mostly utility-based). The best example that comes to my mind is self-assembly. It's an outstanding general problem, but a necessarily interdisciplinary one, involving the engineering of not covalent bonds but weak interactions.

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48. Anonymous on August 9, 2010 10:58 AM writes...

#46 "For 99% of papers, efficiency is not the target, a particular product in suitable quantity for charactarisation be it spectroscopically, biologically, etc, is the target."

I never said it was but in most cases it should be.

"Research chemistry, gram per gram, is hideously inefficient, because it's not a care factor in publishing papers."

But it should be.

I'm interested in this concept of "validation" - I guess this is what academics tell themselves they are doing when embarking on their next bollockomycin project but in most cases this is just hogwash. I'm well aware that there have been a large number of structure reassisgnments as a consequence of natural product synthesis attempts, but does it really add much to the sum total of human knowledge.

Make me a gram of taxol through total synthesis (no relay intermediates or semi-synthetic routes) and you will have achiueved something. Why ? Because it won't be just about scale-up it will be about inventing whole new ways of constructing complexity.

And with the best will in the world artemesin is not a "big arse natural product" and some of the most interesting work in the area has not been on the compound itself, but rather on fully synthetic analogues that try to mimic the mechanism - surely a more valuable exercise than a pointless synthesis of Brevetoxin or Palytoxin.

I'm not anti-natural product synthesis, just anti to the idea that stringing tens to hundreds of linear steps together is in any way an intellectual achievement. I still remember Overman's strychnine synthesis coming out in 1993 because of the sheer brilliance of the route compared to what had gone before. More of that kind of chemistry please, and less of the long-winded rubbish that passes for organic chemistry these days.

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49. mad on August 9, 2010 4:24 PM writes...

In many industries its not about if you "can" do somethign in chemistry its about if you can do it cost effectly and scale it up. And maybe from differnet starting materials. That will always be there.

Also as flashy as astronomy and phyics might be I dont think there are many jobs.

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50. Tyrosine on August 9, 2010 10:18 PM writes...

"I worry a lot about organic chemistry, about the state of the discipline. I worry about the relative lack of grand challenges, and that most academic work is highly incremental"

Your correspondent was entirely correct. And at least some of the blame can be laid at the feet of the modern obsession with measuring "scientific excellence" by publication metrics. Several posters here have mentioned Woodward -- Nobel Prize winner and arguably the father of modern synthetic organic chemistry. Let's have a look at Woodward's career.

Woodward published around 200 papers in a career spanning about 50 years - an average of about 4 papers per year. In the first 10 years of his career he published 24 papers. Even at his most prolific in the early 50's he was only publishing an average of about 7 papers per year.

There's no question about the quality... One of his major contributions "Conservation of Orbital Symmetry", published in 1969 was cited over 2000 times. His average citations per paper is around 100 and his h-index is an impressive 69. And that was in the days when citations were genuine, not puffed up for self-promotion.

But citation rates are a trailing indicator -- Woodward's total citations for the first 10 years of his career are less than 50. With that publication and citation record, Woodward would have hardly even made it to interview for a junior lectureship position these days.

My point is that measuring "excellence" using publication and citation metrics is actually driving chemistry to mediocrity and incremental research. The easiest way to run up publication numbers is to do "safe", ie. incremental, science, replete with lots of self-citations and a few reviews thrown in to boost citation rates.

As far as I can tell Woodward only published a couple of papers out of his doctoral work (without his supervisor as co-author!) and those were several years after his PhD award. Student of today a re pretty unhappy unless they get three or four paper *during* their PhD and they want them in high impact journals (don't get me started on that) as well. Again, this drives incremental research and mediocrity. Our discipline will continue to decline unless we turn around this obsession with publication metrics as a surrogate for quality.

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51. damn academics on August 10, 2010 7:38 AM writes...

what should we work on now?

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52. Dr. Smalls on August 10, 2010 9:01 AM writes...

@#50

Add to the publication metrics the lack of balls the funding agencies have (what? fund something that might *not* work but is really forward thinking??) and it is no wonder why there are issues. ROI is killing science.

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53. DrAli on August 13, 2010 5:31 AM writes...

One comment mentioned looking at the origin of life. If there's one big question that can only be answered using organic chemistry this has to be it. How did small molecules assemble into the building blocks of life? How did they become able to evolve into systems capable of passing genetic information from generation to generation? Orgel's 1970s work was mentioned above but since then there have been great advances by Eschenmoser, Sutherland and others. Organic chemistry is far from being dead as a science for answering big questions.

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54. sponge on August 14, 2010 4:18 AM writes...

I liked natural product synthesis and have been engaged in this kind of research for years. At the same time, I always try to find an academic post back home but discovered that over there, they are all chasing chemical biology or materials science. An inorganic chemist once asked me why didn't I do something "useful"! It is very difficult to put a spin on what we do. I do not intend to offend the materials scientists or chemical biologists but it is rather easy for them to include key words or phrases like solar energy harvesting, molecular switches, protein kinase etc. in their research proposals. They are out there to save the world. These kind of research themes sell well. In addition, we are also partly to be blamed. Far too many people who are engaged in natural product synthesis are purely "molecule bashers". What their research does not contribute any significant improvement to our understanding of organic chemistry.

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55. Matt on August 14, 2010 11:30 AM writes...

I'm scrolling through the comments, and honestly ... I think the biggest detractors to organic chemistry's "wow" factor are the people. I think the angry embittered, cynical, workaholic, martyrs are ruining our cause. The more time I spend being broke, running columns, and ignoring general people, the less inspiration I have that my chemistry can actually provide services to humanity! It also makes another angry embittered martyr for the cause, and now we can't even guarantee them jobs for their narrow minded sacrifice. It makes me ashamed of my Ph. D. in organic chemistry how we discard people. We spend all our time worshiping at the alter of total synthesis narcissists like KCN and enough time selling chemistry to the people.

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56. Anonymous on August 20, 2010 10:07 PM writes...

Organic chemistry...it's great! remember when you got that impossible reaction to finally work after serious man years & stuff? What was your feeling? that's what we're talking about. Success! Keep that feeling and use it in your day 2 day med chem pursuits. recycle if possible!! LOL

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