Editor’s note: Frank Leibfarth is about to embark on a postdoc position and is trying to make his way through the academic maze. Find him contributing to the Sceptical Chymist or continue the conversation on Twitter @Frank_Leibfarth.

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I stand at the cusp of a thrilling and intimidating time in the life of a young scientist. I recently defended my dissertation and I am embarking on a postdoc with the intention to join the academic ranks. The next few years, especially the beginning of an assistant professorship, will be the closest to true intellectual freedom that most scientists have in their career; perhaps the only time to imagine and pursue risky ideas with money untied to the requirements of funding agencies or companies. This is my opportunity to take chances, to think big, to solve pressing problems or, at a minimum, to fail spectacularly while trying.

We, as scientists, possess a specialized and rare set of skills. Few people can say that their training, used correctly, can fundamentally better the human condition. Young scientists not only have the privilege of being in this position, but also the freedom to choose our path forward. But how does one conceive truly innovative ideas, those upon which to build your life’s work, in a relative vacuum? This depends on how we approach and classify scientific research.

Since the creation of the U.S. National Science Foundation on the recommendation and philosophy of Dr Vannevar Bush, most of the developed world has classified scientific inquiry as either ‘basic’ research, purely curiosity-driven work meant to develop general knowledge, or ‘applied’ research, performed in the service of some immediate goal. This model, which permeates how funding agencies allocate money and how popular culture perceives science, presumes the creativity of basic science will be lost if constrained by premature thoughts of practicality. Personally, this one-way street — with basic science and its eventual application at two ends of a linear spectrum ¬— feels limiting.

Donald Stokes agrees. In his book Pasteur’s Quadrant: Basic Science and Technological Innovation, he advocates that understanding and use are better considered in two-dimensions, with the vertical axis representing the quest for fundamental understanding and the horizontal axis referring to the consideration for use. By separating this plot into four quadrants, Stokes asserts that the top left quadrant represents the classic notion of basic research and the bottom right quadrant refers to purely applied research. Stokes gives the examples of Niels Bohr and Thomas Edison as scientists whom occupy these two quadrants, respectively.

The true innovation in Stokes’s classification is the top right quadrant, which he refers to as Louis Pasteur’s quadrant. Pasteur, as Stokes notes, never undertook a study that was not applied; his fundamental contributions to science, however, spawned the entire field of microbiology and forever changed the way we view the cause and prevention of disease. Pasteur’s quadrant illuminates a path where applied goals are not inherently opposed with scientific creativity and rigour. Understanding and being open to this use-inspired basic research has been inspiring for me. It has enabled me to move away from the either/or logic of basic-versus-applied research and think ‘big’ by focusing ‘small’. Choosing a fundamentally new and/or novel phenomenon and uncovering the basic science underlying it can set the stage for translating that knowledge into application.

Use-inspired basic research is also a powerful approach in policy considerations. As austerity becomes the economic policy of choice in countries throughout the world, investments in science are being scrutinized for their ability to maintain a nation’s competitive edge in a global economy (examples here and here). The belief that curiosity-driven inquiry can itself guarantee advancements in technology is sometimes difficult to justify, but mission-oriented research inspired by societal need both protects fundamental science and advances vital economic and social interests.

Like most scientists in my position, I am both excited and uneasy about my impending intellectual freedom. The concept of Pasteur’s quadrant, however, tears down many long-held assumptions about basic and applied research and assures me that I can do both rigorous and relevant science.

Posted on behalf of Aaron Finke

Chemistry lab courses should focus more on method and problem-solving rather than specific techniques, with room for students to “fail” so they can learn from their mistakes. The best approach is to use open-ended experiments that require students to formulate conclusions other than “it worked” or “it didn’t work.” However, these experiments usually require a significant time commitment on the instructors’ part, and so these kinds of experiments are usually only found in labs for chemistry majors with small student enrollments.

My undergrad’s senior capstone project for chemistry majors is a particularly good example of this kind of open-ended science project. In our instrumental analysis lab, teams of three or four were given an item the coordinators purchased from the store — a calculator, a bottle of glue, etc. We were then given questions to answer, such as the identity of the polymer in the packaging, trace metal analysis of the can, the propellant, and so on, which required us to use the instruments and techniques we learned in the semester. Since nobody knew the “correct” answer, sufficient statistical analysis was required to pass muster.

This project was one of the highlights of my undergraduate curriculum, but it required considerable time and effort on the TA’s part- and we had 5 TAs for about 30 students. How can large universities undertake such a project in a lab class with 500 students and 10 TAs?

Melanie Cooper, a professor at Clemson University, has spearheaded a program there to develop a high-enrollment laboratory course that is open-ended and focuses on method and reasoning rather than techniques. In a 2006 J. Chem. Ed. paper (vol. 83, p. 1356), she describes an example project for an organic lab. Each student was given an unknown, and after characterization of the unknown, the student would have to find a procedure for nitration of that unknown using the chemical literature, and justify that procedure before attempting it. Students monitored the reaction by TLC, and noticed that some unknowns reacted faster than others, and some even decomposed if the temperature was not controlled. Students could then collaborate and determine what factors led to such a disparity in reactivity, drawing from concepts learned in lecture and from each other.

This is the kind of project that requires students to think about what they are doing, rather than simply read off a recipe they are given. Furthermore, in such an open-ended project course, there is room for experiments to fail — a luxury that “cookbook” labs, scrambling to finish as many experiments as possible in a semester, do not always have.

Science is a humbling process — most scientists expect some portion of experiments they perform to fail. However, in today’s “cookbook” labs, failure to perform the experiment adequately leads to a lower grade in the course, leading many students to believe that all practical science is based in absolution — when an experiment fails, it is your fault, no matter what. (Then some of these undergrads join research labs, and have to learn the hard way that cutting-edge science doesn’t work like that!) Open-ended lab experiments give students the opportunity to perform “real” science in a more controlled environment.

Posted on behalf of Aaron Finke

Chemistry lab courses should focus more on method and problem-solving rather than specific techniques, with room for students to “fail” so they can learn from their mistakes. The best approach is to use open-ended experiments that require students to formulate conclusions other than “it worked” or “it didn’t work.” However, these experiments usually require a significant time commitment on the instructors’ part, and so these kinds of experiments are usually only found in labs for chemistry majors with small student enrollments.

My undergrad’s senior capstone project for chemistry majors is a particularly good example of this kind of open-ended science project. In our instrumental analysis lab, teams of three or four were given an item the coordinators purchased from the store — a calculator, a bottle of glue, etc. We were then given questions to answer, such as the identity of the polymer in the packaging, trace metal analysis of the can, the propellant, and so on, which required us to use the instruments and techniques we learned in the semester. Since nobody knew the “correct” answer, sufficient statistical analysis was required to pass muster.

This project was one of the highlights of my undergraduate curriculum, but it required considerable time and effort on the TA’s part- and we had 5 TAs for about 30 students. How can large universities undertake such a project in a lab class with 500 students and 10 TAs?

Melanie Cooper, a professor at Clemson University, has spearheaded a program there to develop a high-enrollment laboratory course that is open-ended and focuses on method and reasoning rather than techniques. In a 2006 J. Chem. Ed. paper (vol. 83, p. 1356), she describes an example project for an organic lab. Each student was given an unknown, and after characterization of the unknown, the student would have to find a procedure for nitration of that unknown using the chemical literature, and justify that procedure before attempting it. Students monitored the reaction by TLC, and noticed that some unknowns reacted faster than others, and some even decomposed if the temperature was not controlled. Students could then collaborate and determine what factors led to such a disparity in reactivity, drawing from concepts learned in lecture and from each other.

This is the kind of project that requires students to think about what they are doing, rather than simply read off a recipe they are given. Furthermore, in such an open-ended project course, there is room for experiments to fail — a luxury that “cookbook” labs, scrambling to finish as many experiments as possible in a semester, do not always have.

Science is a humbling process — most scientists expect some portion of experiments they perform to fail. However, in today’s “cookbook” labs, failure to perform the experiment adequately leads to a lower grade in the course, leading many students to believe that all practical science is based in absolution — when an experiment fails, it is your fault, no matter what. (Then some of these undergrads join research labs, and have to learn the hard way that cutting-edge science doesn’t work like that!) Open-ended lab experiments give students the opportunity to perform “real” science in a more controlled environment.

[Joining The Sceptical Chymist is our latest guest blogger, Aaron Finke. A grad student at the University of Illinois, Urbana-Champaign, he works on polyphenylene dendrimers and hyperbranched polymers. You may know Aaron better as Excimer from his posts at Carbon-Based Curiosities.]

I will be focusing most of my energies on these guest-blogging posts to chemical education. This past semester, I had the opportunity to be in charge of a large laboratory course — specifically, the organic chemistry lab course for non-chemistry majors. The “behind-the-scenes” experience I got was an eye-opening one in many ways, from a pedagogical, professional, and personal perspective. I will attempt to recount my experiences and lessons learned here.

A large portion of the students in my lab course were pre-medical and pre-veterinary students, and took it to satisfy the requirements for getting into their respective programs. A majority of the students took this course with the full recognition that it was merely a hurdle for them — a hoop to jump through with no relevance to the future careers to which they are aspiring.

I can’t blame them for having that mentality. The course is an organic chemistry laboratory course, designed to introduce procedures and methods in the synthesis and purification of organic molecules… skills that are mostly irrelevant to those outside of organic chemistry. They learn and perform techniques like extraction, column chromatography, recrystallization, basic organic synthesis, and so on. I use a majority of these techniques every day. But I am an organic chemist. The 500 students in my class are not. It is highly unlikely they will actually use the specific skills implemented in the course, unless they plan on distilling their own whiskey! [Editor’s note: This is illegal in many countries]

The skills students SHOULD be learning in laboratory classes are more general, and, with a “cookbook” chemistry curriculum, are not developed in any capacity. A report which came out June 4, co-authored by the Association of American Medical Colleges (AAMC) and the Howard Hughes Medical Institute (HHMI) and entitled “Scientific Foundations for Future Physicians”, outlines eight core competencies that pre-medical students should demonstrate before entering medical school.

The second competency listed concerns lab courses: “[The student should] demonstrate understanding of the process of scientific inquiry, and explain how scientific knowledge is discovered and validated.” Interestingly, the guidelines indicate only three chemistry-specific goals: gathering primary data for mixtures of compounds, using stoichiometric analysis to determine yield, and, most interestingly, demonstrate a knowledge of instrumentation such as NMR, mass spec, X-ray, etc. These goals, ideally, should be implemented with a focus on discovery, making conclusions, and understanding error.

Most pre-med organic chemistry lab experiments focus on only one of those three things — characterization without application; or synthesis without full characterization — and I dare say few, if any, display a heavy focus on instrumentation. This report acknowledges that advances in medical science and medicinal chemistry rely heavily on modern instrumentation, and yet outdated chemical identification methods are more heavily emphasized in most basic lab courses. When was the last time anyone had to make a semicarbazone derivative of a ketone outside of a lab course? These are secondary or tertiary methods of identification to modern organic chemists. It is enough to know that they exist. But if medical students are to understand the modern literature, they should be taught modern chemical methods. And in their o-chem labs, they are not.

In my next post, I’ll discuss what some chemistry educators are doing to fix the problem of relevancy in lab courses.

[Posted on behalf of Aaron Finke]

[Joining The Sceptical Chymist is our latest guest blogger, Aaron Finke. A grad student at the University of Illinois, Urbana-Champaign, he works on polyphenylene dendrimers and hyperbranched polymers. You may know Aaron better as Excimer from his posts at Carbon-Based Curiosities.]

I will be focusing most of my energies on these guest-blogging posts to chemical education. This past semester, I had the opportunity to be in charge of a large laboratory course — specifically, the organic chemistry lab course for non-chemistry majors. The “behind-the-scenes” experience I got was an eye-opening one in many ways, from a pedagogical, professional, and personal perspective. I will attempt to recount my experiences and lessons learned here.

A large portion of the students in my lab course were pre-medical and pre-veterinary students, and took it to satisfy the requirements for getting into their respective programs. A majority of the students took this course with the full recognition that it was merely a hurdle for them — a hoop to jump through with no relevance to the future careers to which they are aspiring.

I can’t blame them for having that mentality. The course is an organic chemistry laboratory course, designed to introduce procedures and methods in the synthesis and purification of organic molecules… skills that are mostly irrelevant to those outside of organic chemistry. They learn and perform techniques like extraction, column chromatography, recrystallization, basic organic synthesis, and so on. I use a majority of these techniques every day. But I am an organic chemist. The 500 students in my class are not. It is highly unlikely they will actually use the specific skills implemented in the course, unless they plan on distilling their own whiskey! [Editor’s note: This is illegal in many countries]

The skills students SHOULD be learning in laboratory classes are more general, and, with a “cookbook” chemistry curriculum, are not developed in any capacity. A report which came out June 4, co-authored by the Association of American Medical Colleges (AAMC) and the Howard Hughes Medical Institute (HHMI) and entitled “Scientific Foundations for Future Physicians”, outlines eight core competencies that pre-medical students should demonstrate before entering medical school.

The second competency listed concerns lab courses: “[The student should] demonstrate understanding of the process of scientific inquiry, and explain how scientific knowledge is discovered and validated.” Interestingly, the guidelines indicate only three chemistry-specific goals: gathering primary data for mixtures of compounds, using stoichiometric analysis to determine yield, and, most interestingly, demonstrate a knowledge of instrumentation such as NMR, mass spec, X-ray, etc. These goals, ideally, should be implemented with a focus on discovery, making conclusions, and understanding error.

Most pre-med organic chemistry lab experiments focus on only one of those three things — characterization without application; or synthesis without full characterization — and I dare say few, if any, display a heavy focus on instrumentation. This report acknowledges that advances in medical science and medicinal chemistry rely heavily on modern instrumentation, and yet outdated chemical identification methods are more heavily emphasized in most basic lab courses. When was the last time anyone had to make a semicarbazone derivative of a ketone outside of a lab course? These are secondary or tertiary methods of identification to modern organic chemists. It is enough to know that they exist. But if medical students are to understand the modern literature, they should be taught modern chemical methods. And in their o-chem labs, they are not.

In my next post, I’ll discuss what some chemistry educators are doing to fix the problem of relevancy in lab courses.

[Posted on behalf of Aaron Finke]

Posted on behalf of Retread

People speak of information pretty glibly. Claude Shannon defined it as various combinations of bits (binary digits which can be ones and zeros) for electronics 61 years ago in a paper written about his classified work during World War II. Neuroscientists speak of information processing by the brain as the way it manipulates its input (a series of action potentials in nerve fibers which are about as close to Shannon’s ones as you can get).

So that’s what information is. But we really don’t understand the entities (electronics, the brain) which actually do the processing terribly well. Consider first solid-state electronics, which catches Shannon’s ones and zeroes. Just how well do we understand the solid state? Not very well according to Robert Laughlin, Nobel physicist, in his book “A Different Universe: Reinventing Physics from the Bottom Down”. Quantum mechanics is now introduced to chemists in college, and I assume a course is obligatory in graduate school these days. Laughlin says it doesn’t really matter in understanding the solid state, in the same way that the underlying chemical structure of the zillions of organic compounds which have been crystallized does not in any sense matter in explaining the crystalline state. All that matters, is that each molecule adopts the same shape regardless of what that shape is (this is why proteins are hard to crystallize). The book will make your head swim.

How about the brain? Do we understand it? Ask your friendly neighborhood neuroscientist why we need sleep, or better, exactly how and where in the brain memories are stored. You may hear a few mumbles about reverberating circuits or long term potentiation, but we really don’t know. Although the brain has 10^10 neurons and probably 10^13 synapses (which is how neurons talk to each other), we can’t use statistical mechanics to understand it. Amazingly, even in the case of the monatomic ideal gas, the atoms are assumed not to interact with each other (other than collide), and their energies are sufficiently low that electronic excitation isn’t possible. Just as a list of the 10^23 positions and the 10^23 momenta do not explain the pressure of a gas, the list of what the 10^13 synapses are doing every millisecond, in addition to being incomprehensible, would not explain in any sense how and where memories are stored.

Where does chemistry come in? Consider the chemiotics posts of 9 Feb and 20 Jan. They say something profound about information, and not just in the cell. The information in DNA depends on how it’s read (one way by the ribosome reading mRNA to make a protein, another by the splicing machinery to determine what mRNA is made, and a third way by microRNAs to determine how long the mRNA hangs around). Only through chemistry can the reader of the information be understood, and I think chemists understand the readers fairly well. I’m not sure if Shannon’s concept of information entropy could even be applied to a DNA sequence being read 3 ways at once by different molecular machines. All discussions of information I’ve seen, pretty much ignore what’s actually doing the reading.

Galileo famously said, “The universe cannot be read until we have learnt the language and become familiar with the characters in which it is written. It is written in mathematical language”. Well, the information we have the best chance of understanding (because we understand the reader) is written in the language of chemistry. Thus do chemists stand astride the Cartesian dualism of materiality and the nonphysicality of information.

Posted on behalf of Retread

Organic chemists love mechanism, subtlety and specificity. Books have been written about pushing arrows. Medicinal chemists are always worrying about making molecules which they can dock into either the active site or an allosteric site of a target protein. The fit must be quite close, and a recent post over at In the Pipeline notes that ‘You’ll have whole series of compounds that have to have a methyl group at some position, or they’re all dead. Nothing smaller, nothing larger, nothing with a different electronic flavor: it’s methyl or death.’

So making an organic molecule that responds to the physical properties of its surroundings – rather than the bonding structure of the molecules surrounding it – stands this sort of work on its head. As usual, nature got there first. Here are two examples.

Cells need to respond to the amount of cholesterol they contain, and make more if lacking. Cholesterol is poorly soluble in water, being found mostly in membranes. Here cholesterol functions as a fluidizer, making the long hydrocarbon chains of phospholipids and other lipids more disordered in order to fit around it. So cholesterol doesn’t exist just to make pharmaceutical companies rich. A similar mechanism probably explains why unsaturated fatty acids (such as oleic acid) found in membranes have cis rather than trans double bonds (and in the middle of the chain to boot), making them harder to pack.

So if your membranes have less cholesterol they become stiffer. This stiffness is sensed in some way by several membrane embedded proteins (SCAP, INSIG1). SCAP then moves SREBP, another membrane embedded protein (along with its associated membranes) to another site in the cell where it is cleaved. It took years to figure out how water got inside the hydrophobic environment of the membrane to cleave (hydrolyze a peptide bond) SREBP. One of the SREBP cleavage products is then able to leave the membrane, migrate to the nucleus, bind to DNA and turn on genes in the cholesterol synthesis pathway. Elegant no?

A second example. The DNA in our cells is under constant chemical attack. Ultraviolet light produces cyclobutane dimers of adjacent pyrimidine nucleotides. Nucleotides fall off the backbone or have attached molecular fragments which alter their stereochemistry. Then there are the mismatches (an A or a T pairing with G rather C etc., etc.). Somehow, proteins scan DNA for these lesions (and find them). One such protein complex is DDB1/DDB2 (see here and here) which recognizes a very broad range of DNA lesions which are subsequently targeted for repair. DDB1/DDB2 binds to pyrimidine dimers (which distort the helix) and to DNA with crosslinked bases (e.g., due to cisplatin, psoralen), and also to DNA lacking nucleotide bases (just the opposite of crosslinked DNA).

How can one protein complex do all this? One theory has it that DNA lesions are recognized by their increased flexibility (because of decreased stability of base pairing and stacking in damaged DNA). This enables DNA lesion finding protein complexes such as DDB1/DDB2 to target a broad range of DNA pathologies for repair (without recognizing them specifically). They are binding to the effect of chemistry, rather than the chemistry itself, e.g., they are binding to a physical property of damaged DNA rather than its chemical structure.

Only the chemist can fully appreciate the wonder of what’s going on under the cellular hood. In this we are fortunate, even if regarded as somewhat grubby by everyone else. Pascal’s thinking reed and all that.

Posted on behalf of Sugar Daddy

With the changing of the guard in Washington, late-night night television hasn’t quite been the same. I guess the new guy in charge is a harder target for comics. Anyway, to a certain extent, the late-night hosts have been turning their attention elsewhere, and eventually chemistry was bound to make it. In this clip, Conan O’Brien draws attention to, among other things, the discovery of a fourth form of pure elemental boron.

The humor in the clip originates from a recent New York Times article that had mistakenly counted the number of pure forms of boron, and Conan was mocking them for not being able to correctly count to four. The surprise for me was that Conan whipped out a big poster board with crystal structures of the various forms of boron and then started to describe them in rather gory scientific detail. I don’t think this will help the public understand chemistry any better, but it’s better than nothing, I guess. Plus, he’s funny.

Posted on behalf of Retread

Remember noncoding DNA? For protein that is. That’s 98% of our genome. It now appears that at least half of our genome is transcribed into RNA. Is this a case of transcription machinery gone wild? One type of RNA made from the 98% is called microRNA (after it is cut from a larger precursor). MicroRNAs are only 21-23 nucleotides long. They aren’t used to make proteins (which would be at most 7 amino acids long anyway). Instead they bind to complementary sequences in messenger RNA by classic Watson-Crick base pairing, and inhibit the translation of the mRNA into protein by the ribosome. So although microRNAs don’t code for proteins, they help determine how much of them are made.

Until recently, microRNA binding to mRNA was thought to occur at the tail end (which does not code for protein). Two recent papers show that microRNAs also bind to the amino acid coding sequences of some proteins [Nature vol. 455 pp. 1124-1128, 2008 and PNAS vol. 105 pp. 20297-20302, 2008]. Change one synonymous codon to another, and the microRNA no longer binds and the level of the protein changes. So this is the third code written into our DNA.

What’s so remarkable about that? Pop a DVD of a movie into a player. You are given choices of subtitles, language, etc… All these modalities are coded on separate tracks and blended together by the player after you choose. DNA is just one track and is coding for subtitles, sound and pictures by the same sequence of nucleotides. A given DNA sequence is capable of being read at least 3 ways — amino acid, exonic splicing enhancers and inhibitors, and microRNA — (and who’s to say that these are the only ways DNA can be read).

The examples in the Nature paper are far from trivial as they involve Nanog, Sox2 and Oct4. So what? These three genes are crucial for stem cell function, and with a fourth have been used to transform normal cells into ‘stemlike’ cells (induced pluripotent cells — iPSs). What could be sexier than that? MicroRNA-control of these proteins has to be important.

There has recently been a good deal of interest in diversity oriented synthesis of small molecules — see [Nature vol. 457 pp. 153-154, 2009] and the ‘In the Pipeline’ blog post of 20 Jan, along with the more than 40 comments it brought forth. The hope is to create a wider variety of small molecules which can interact with proteins than we’ve been used to — and which might be useful drugs.

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