Quoteworthy


...quaecumque sunt vera, quaecumque pudica, quaecumque justa, quaecumque sancta, quaecumque amabilia, quaecumque bonae famae, si qua virtus, si qua laus disciplinae, haec cogitate.
-- Phil. 4:8
Showing posts with label chemistry. Show all posts
Showing posts with label chemistry. Show all posts

A Structural Biologist's Manifesto

"So, what are you studying?" Depending on who is asking, the length of my answer would vary. See, since I go to grad school, quite a number of people are asking me that; and answering 'Biomolecular NMR' would draw some blank stares.
So, go back a little: Chemistry. Ah, my undergrad major, and since my lab uses analytical chemistry technique (i.e. Nuclear Magnetic Resonance) to probe biomolecular structures, this answer is not too far off the mark.
"So why are you in the School of Biology?" Ahem. Here we go again.
So, the slightly longer and my supposed official areas of study: Structural and Computational Biology. I think I shall reintroduce my clockwork analogy here. Imagine a clockwork with all its gears running inside. If one would want to know how exactly the clockwork mechanism work, one would want to take it apart and see the gears; how they are connected together, what are their shapes that fit each other so that the concerted mechanism is running. Now, every living thing is also a machine, a biochemical machinery, that, like a clockwork, consists of tiny, tiny parts that are grinding away and give rise to life as we know it. Ideally we want to map how these biomolecular gears interact with each other (i.e. the interactome). Prior to that we would want to know how these tiny gears look like. The structures of these tiny gears are then what the structural biologist would like to know.
'To know' here, as in all areas of science (or anything, really), should be interpreted philosophically. The usual limit of what a structural biologist want to know goes beyond 'having a visual representation'. Sure, it's nice to know what these biomolecules look like since we normally can't see them with naked eyes. But blobby blobs at crappy resolution (say, 15 Å) doesn't tell much. Like a blurry text on a document for example; it's unreadable. What we would like to know, ideally, is the visual representation at the resolution of individual atoms (i.e. atomistic resolution). The blurry text on your document now gains some sharpness; now you can distinguish individual letters; it's now legible. Often, this is sufficient to establish how it behaves, how it interacts with, say, water molecules, metal ions, drug molecules, or other biomolecules.
To even arrive at this point is an accomplishment (to illustrate, resolving a previously unresolved structure of a big protein and analysing its structure-function relationship may occupy the whole PhD thesis, to give you a sense of scale). Could we do better, you ask? Erm, there's actually some problems -- hitting the philosophical wall, so to speak. Let me explain.
*WARNING: TECHNICAL TERMS AHEAD*
So, there are two common techniques used to probe biomolecular structures. (Oh, when we are talking about biomolecules, we mostly talk about proteins -- the biomachinery mostly comprises them).
The first is X-ray diffraction. It works by interpreting the diffraction pattern of X-ray by electron density of the atoms that make up the biomolecule. Since the atoms are arranged in a particular way for a biomolecule, the diffraction patterns are unique to each biomolecule; and long story short, the X-ray crystallographer would be able to construct back the electron densities of the biomolecule, thus she would able build a model of the biomolecule.
Now, problem #1, for a nice diffraction pattern, you would need repeating units, so you would need crystal of your protein, and crystallising a protein is honestly a PITA. Arising from that, problem #2, you would try a lot of different conditions until you find one that is suitable for crystallisation -- who is to say that that particular condition doesn't affect the structure of your biomolecule? Still arising from problem #1, the protein in say, your body, is in aqueous environment, but in your crystal it is obviously in solid -- problem #3, who is to say that your protein structure is not altered by crystal packing, and problem #4, your final structure would be a static snapshot of the structure frozen in the crystal, while the structure in solution must be a lot more wiggly-diggly -- do you now claim you 'know' the structure? (There, your epistemological wall). Problem #5, most of the atoms comprising a biomolecule -- C, O, N, S, Se, and some metals -- have nice, fat electron densities, but that ubiquitous Hydrogen, the most abundant element in the Universe of things living and non-living, does not. As such, H atoms are not visible in the crystal structure. Problem #6, so are regions of the biomolecule that does not form regular repeating units (most likely because they are floppy).  Problem #7, when you are matching atoms to your electron density map, some are ambiguous (e.g. you can point sidechain A at this orientation, it fits ok, flip sidechain A 180° and it still fit ok, even though on one orientation it's N but the other is O -- since N and O have similar electron densities).
So your typical X-ray structure file would miss its H's and its flexible regions (the termini are usually susceptible); some sidechains may not be at their correct orientation; and there's only one frigging, static frame. Would you now consider you 'know' the structure?
Oh, then there's NMR. The laypeople would be more familiar with MRI (Magnetic Resonance Imaging). Indeed the underlying principle is the same: both exploit the same phenomenon, i.e. nuclear magnetic resonance which arises from nuclear spin (which belongs to the wonderful, you-will-understand-better-if-you-don't-try-to-understand-it world of quantum mechanics (for instance, there's no way to visualise quantum spin)). Long story short, NMR yields a set of restraints. If in X-ray crystallography one needs to fit the biomolecule to the little pockets of electron density, in NMR one needs to fit the molecule to satisfy these restraints. So you would have to know the amino acid sequence of your protein. So then you have a totally linear peptide -- make the peptide explore different conformations to satisfy the restraints, a game of Twister if you will. What you end with would be a set of conformers, which would be ranked according to their energy. Usually the first 20 low-energy conformers are deposited in public domain. The fact that there is a set of conformers, called an ensemble, is important. By aligning the conformers in an ensemble, it's usually clear which region is flexible -- the deviation for that particular region would be more pronounced across the conformers. So an NMR structure would have its H's, all amino acids visible and it's not a static snapshot (cf. X-ray structure). Also, if you do solution NMR, it's may be possible to as close to physiological condition as possible (may not be totally tractable because of limitation in NMR setup itself, e.g. NMR signal at high pH condition decays too fast).
While seemingly answering to all X-ray crystallography's woes, the NMR spectroscopist faces a totally different set of problems. First off #1, NMR is an indirect technique, unlike X-ray diffraction which directly constructs a map of electron densities. So NMR structure doesn't really have a concept of 'resolution', which makes it kind of hard to assess the quality of a structure. So, you have made your protein play a game of Twister to satisfy your restraints, now #2, the quality of restraints -- if I see a flexible region in the ensemble, is it really flexible region, or I didn't apply enough restraints, that's why it's fuzzy? #3, the game of Twister is called restrained molecular dynamics, basically a computer simulation. Of course, it's only possible to incorporate approximations and assumptions, not the whole physical law shebang, into the software. Some of those may not be appropriate and may affect the resulting structure in a significant way. There are some technical obstacles as well, like how the protein of interest needs to be isotopically labelled with NMR-active nuclei (15N, 13C). The final step of reconstructing the structure is tedious both for X-ray crystallography and NMR spectroscopy -- so that adds to the time needed to produce a good 3D representation of a protein. 
So, for the umpteenth time, after successfully determining a structure, the structural biologist should ask, metaphysically, Do I 'know' the structure?

Science, people. 

That's it. Next time I will just reply, "I do Science."  

Clockworks: The Story of Drugs — Part 1

In this installment, I will discuss why it is difficult to discover, design and develop a drug, in view of our current knowledge of physiology.

ResearchBlogging.org
With numerous, intertwined reactions happening, our body is a complex clockwork of biomachinery gears. What do you do, then, if some gears fail—that is, if you got sick? On one hand, it is a consolation that many gears are what biologists call 'redundant', which means that it's alright that a certain gear fails, because there are other gears that can take over its function. On the other hand, due to the intricacy of the gears, it is hard to pinpoint which gear is the problem, let alone fixing it. And the sheer number of gears: ICD-10 classifies tens of thousands diagnoses — tens of thousands ways the gears can fail — and those are only the ones we know; how about those we don't? Granted, some are not caused by our own gears failing, but by interferences of other, pesky gear systems: viruses, bacteria, misfolded proteins, errant microbiome, etc.; but the sense of magnitude is there.

The Natural Philosopher's Guide to Science

I think chemistry so be a sub-discipline of physics and be called "valence shell dynamics".
It doesn't deserve a separate Nobel prize category any more. It is largely predictable by theory as this current prize was. Yes, the experimental discovery should be awarded too
-- A comment

You could almost hear it. The collective sigh of chemists all over the world, I mean, over similar sentiments as above. Of course as a chemist-in-training I should say something in apologia. Though as soon as I said that, I realised that the epistemological perspective of the field is nowhere found in my training. So treat this piece as what I thought I knew about chemistry at the meta-knowledge level, and why I found the aforementioned comment distasteful, to say the least.
I will begin with definitions, like all good epistemological pieces should. To be sure, physics is the study of physical things and how they behave, in other words, the physical laws. Technically then, chemistry is certainly a subsidiary of physics, but so is biology, geology, climatology and every other subject studying the tangible, because the tangible obey physical laws. Such classification then becomes useless, the field too bloated, which defeats the purpose of classification in the first place.
As such, we must recognise the two kinds of classifications here: the technical one and the utilitarian one. So, an attempt to unify chemistry under the grand umbrella of physics is technically proper but not useful. Utilitarianism here is of course anthropocentric -- Man is the measure of all things, said Pythagoras. The study of behaviours of valence electrons has implications in the chemical industries -- from paints, fertilisers, cosmetics, foodstuff, to drugs -- that are paramount to our lives that they need a separate category. This is even truer for the engineering fields, the direct spawns of physics, that the industry would benefit from clear distinctions. As important is the utility to the academic learning. The massive amount of knowledge has to be compartmentalised -- the size of the field should be roughly learnable within a four-year bachelor's degree. Imagine if a physics degree also requires you to learn chemistry to the level of the current chemistry degree -- how long would that take, and how useful is that for the learner who doesn't intend to go to grad school? And the utility values to the industry and academia are intertwined. The training during the four-year bachelor's should be at least enough for the learner to have a basic grasp of the field to start out in the industry (or his curiosity piqued enough that he would choose to go to grad school, but that's another story).
Sure, the divisive line blurs when one talks about physical chemistry for example. Does thermodynamics belong to the realm of physics or chemistry? Sticking to utilitarian value, one should resist classification then, and embrace both labels, because, why not? The separate classification of chemistry should serve to make clear; when it does not serve this purpose and potentially misleads instead, then the classification has ceased to have any utility.
In a talk I attended where Aaron Ciechanover, 2004 Nobel laurate in Chemistry, was the speaker, someone, evidently an organic chemist grad student, asked about the role of synthetic chemist in increasingly biological approach in drug industry. He gently rebuked the questioner regarding the absurdity of such division. In short, he lamented the current state of affairs where science departments are so isolatedly fragmented they are not communicating and collaborating with each other. When I think of these things, strangely enough I am reminded of Victor Frankenstein, whom Shelley described as a 'natural philosopher' if my memory serves right, and his creature. That there was a time when the hard sciences are united on a front called natural philosophy, before it has inflated to the the sewing of appendages that barely fit each other, the chimeric monstrosity it is today.
-- 
Recapitulation so far: It is of utility value to have chemistry as a separate field from physics. This argument may not apply to other fields, so I'm going to offer another argument that applies in all cases. First, if you haven't seen the xkcd's Purity spectrum, go see. Hoewever, as you might suspect, chemistry is not just applied physics, biology is not just applied chemistry and so on. You see, at some point, neuronal connections (biology), neurotransmitters (chemistry), and a bunch of other stuff, as a system, gains enough complexity to become your mind, your consciousness -- picture gestalt, that which the whole is greater than the sum of its parts. You can't go from physical laws to understanding schizophrenia because the interactions involved have become intricately, impossibly complex to unravel. Such property of complex systems is called emergence, and fields are systems of knowledge. Consequently, while you can say how pure your field is compared to to others, it doesn't make one field any more complex than the others, thus any more worthy of study compared to others.
Bottom line is: dividing sentiments are not useful. There is no point in arguing whose field is more significant. What the scientist must do is make distinctions when necessary and useful, and not make them when unnecessary and useless. Carry on that spark of lightning that keeps a burning fire inside Frankenstein's creature's heart; that keeps him alive, that leads him to search himself, that pushes him to wrestle with his creator, that makes sewn appendages move as one.

Apologia pro semita meo

Or defense for my (university) course. Or something like that.
Looking at my writing alone, one probably cannot tell that I am actually a chemist-in-training. 
I have been told for ever that I belong to the science stream. I suppose I do. I always excel in the sciences, my maths is not so bad, and am mostly a creature of logic. Nevertheless I have always suspected that I have some penchant for the Arts, if only an inkling of it. Take my linguistic pedantry; it's been there since I was at junior high level. 
A former teacher said that a person should not be pigeon-holed. That is something I'll always remember, since it confirms my aforementioned suspicion. To label a person as science person or humanities person is just shallow thinking, Of course, it is alright to categorise for certain purposes, say, for education streaming or screening potential employees, for example. But many cannot see the underlying complexities beneath the labels, and end up seeing people as caricatures of sorts; inadvertently oversimplifying and degrading them.
So, despite my proficiencies in seemingly mutually exclusive areas, I ended up in the science. Why? Because, as those who have gone through it can tell you, you can only choose a narrow area. I should digress a little bit to describe my education philosophy. One of my students asked me before, why he has to do English, or Maths, or other subjects, for that matter. I answered, because a person has to be equipped with all areas of knowledge until certain level. At least junior high level, or if you can, high school level, in my opinion. This level is arguable, but I think the paramount criteria are: 1) It is enough to get by in life, 2) It gives enough glimpses of the area in consideration to stimulate interested students to specialise in it. You have to specialise, simply because the amount of human knowledge is too enormous that one cannot know everything in-depth. This vantage view of education is illustrated nicely here.
Next question, why science not other things? (Note that I do not differentiate between physics, chemistry, or biology here, simply because just as you should not pigeon-hole people, you should not compartmentalise science, if you can afford not to). Take a look at my process of elimination. Take into account my nature: I am quite pragmatic, but not shallow; and most of all, am a pursuer of knowledge. I crossed off the humanities, since I doubt I can make a decent living out of it; besides I have greater talents for science. I crossed off business since I do not want to end up as money-making machine. I have read accounts of people feeling empty despite having great wealth (more like, from literary works. Literature is a lens on humanity, more on that next time). I thought to myself, why wasting time learning about laws that can change. Perhaps such is the nature of the said emptiness, the accomplishment of nothing. Another reason that I can put up quite eloquently, if I may say so myself, is that the financial and economic systems are just creations of man, that is, artificial and transient. The laws of nature that science seeks after, on the other hand, are enduring, and will be there as long as this world as we know it exists. To this, a friend countered: but money makes the world goes round. To that, I quipped: perhaps, but I know angular momentum sure does.
Why not engineering? I have already revealed a little that I am interested in the inner working of the universe, more so than applying it into design, to produce technology. I am more interested to be at the frontiers of knowledge, and make a little dent on the current boundary. But the very fundamentals are also not for me. In science and engineering tree, maths is the root; physics, lower stem; chemistry, upper stem; biology, branches; engineering, fruits. I chose chemistry because of its centrality; there is balance between the fundamentals and the applications.
Academia, then. First, I enjoy teaching. Second, as I said, I want to be at the frontiers of knowledge, so I have to do research. I have to admit that the prestige of professorship is also quite alluring. But a darker reason is that I am just plain dastardly. I want to deal with the world from the the lofty ivory tower, dealing with living indirectly, cocooned by the scientific bubble. Say what you may, but I am of the opinion that there is a need for scientists to be separated from the 'world' at large, even though the separation is artificial. In The Glass Bead Game, Herman Hesse depicts a world where this separation is even made geographical. Castalia is the central of academia, much like Vatican is the central of Catholicism. Castalia is called 'aristocracy of the spirit', which has an inkling of elitist connotation. Yes, the separation is unnatural, nevertheless necessary, to protect the scholars from 'money, fame, rank'. Not for everyone, but I feel that it is for me. Deep down, I am just fragile: I don't have the ruggedness to take on the world by its horns; it will break my spirit.
Ultimately, whatever field you are pursuing, keep in mind your purpose. Mine is the pursuit of knowledge, truths that are everlasting. Then to pass on this knowledge for generations to come. 
That you are here — that life exists, and identity; 
That the powerful play goes on, and you will contribute a verse.
-- Walt Whitman

Lexical Order

If you have shelved your thermodynamics at the back of your mind, go retrieve it. Done?
ΔfH
According to the order of appearance: change, formation, enthalpy, standard. 
But lo and behold, you are supposed to read that as: standard enthalpy change of formation. How can that be?
This is because English language adopts lexical order which does not really follow natural thinking process. First off, languages can be divided into two according to the lexical order: modifier-modified and modified-modifier. English belongs to the former, since the modifier precedes the modified. Consider the phrase:
beautiful girl
girl is the noun, the modified, while beautiful is an adjective, so it is an attribute, a modifier.
In Swahili, the same phrase would be (courtesy of Google Translate):
msichana mzuri (literally, girl beautiful, preserving the lexical order)
Note that now the modified precedes the modifier.
As English speakers we probably do not realise how unnatural is the English lexical order. If you think about it, the main idea must be the modified, while modifiers are just attributes. If we are talking about a 'beautiful girl', we are talking about a girl, not a beautiful.
Our mind is usually concerned with the bigger picture first, i.e. the modified; while details, the modifiers, can be filled later. Is there evidence that this is the natural way of thinking? We write symbols that way. Again, look at the same symbol of  'standard enthalpy of formation':
ΔfH
Note that the modified is change. The main modifier is enthalpy. Thus it is a change -- what kind of change? Enthalpy change
Other modifiers, formation and standard, appear as subscript or superscript. f subscript is appended after change because formation specifies the type of change. (Digressing a little bit: This is the new IUPAC convention. Last time, the f subscript used to be placed after the thermodynamic state function. This is not very accurate since, as mentioned, formation is the attribute of change rather than that of enthalpy. IUPAC actually pays attention to proper lexical order!). Nought superscript is more like the modifier to the whole thing, like thus: fH)O . 
Having said all that though, it languages do have ways to reverse lexical order. English uses 'of' to place modifier after the modified:
girl of unworldy beauty
While Japanese uses the familiar 'no' (), which performs very similar functions to 'of'. This though, one must admit, is kind of unwieldy. The rendering of our symbol if the order of appearance is to be followed would be:
Change (of formation) of enthalpy, in standard conditions
There is an alternative argument to the 'unnatural' argument, which is to say that the modifier-modified languages put more importance, then, in the details rather than the big picture. Language and culture are intertwined, as I wrote quite lengthily before. Language is the frame on which thoughts are built upon, so its structure will influence the product of thoughts, i.e. culture, in some ways. We can extrapolate, say, that users of modified-modifier languages are more individualistic than they are socialistic, because they are more concerned with details. This conclusion is, of course, far-fetched. However, you may be surprised that there is actually correlation of sorts: A lot of Western languages are actually modifier-modified and the Western culture tends to be more individualistic. 
But then again, as I pointed out before, you have to be aware that indeed language influences culture, but the other way is also true; the two are intricately intertwined. Like nature and nurture. Ouroboros-like.

The Captain and the Ship Analogy

When explaining about why emission spectrometry is more sensitive than absorption spectrometry, my professor shared this analogy:
Imagine a ship and its captain. If we were to measure the weight of the captain, how would we go about doing that?
Well, we can weigh the ship with the captain onboard. Then weigh the ship sans the captain. Substract.
Otherwise, we can just extract the captain from his ship, then weigh him.
Silly as it sounds, the former is actually what we are doing in absorption spectrometry. Shine light onto sample. Measure the light coming out. Subtract to get the amount absorbed by the sample. This results in a lot of background noise because the difference between what comes in and out is very little, like the weight of the captain.
In emission spectrometry, the source of photons is essentially the sample itself, so background noise is essentially zero. (Not exactly zero, because there may be scattering of the incident light used to excite the sample, e.g. fluorospectrometry. If excitation is by high energy electrons, then noise is probably zero, but there may be other factors)
I think this analogy does not only apply to analytical chemistry but also a lot of other things. There is a concept of big and small here. The ship is big, the captain is small. The presence of the big distorts the measurement of the small. Big and small is kind of a motif in chemistry. You see that in HSAB theory and of course, in regioselectivity explanation of Diels-Alder reaction in terms of coefficients.
Also, relativeness. The ship with or without the captain weigh roughly the same. So the weight of the captain is only negligible because it is being juxtaposed with the weight of the ship.
Chemistry being one perspective on the inner workings of the universe, you can expect the same principle to be applicable in real life. The other day another lecturer found that the computer in the lecture hall has problem with connection to the projector. His solution? Switch to another hall. While he can just borrow a laptop, from a student or the IT office down the corridor, to connect to the projector.
It's like being aboard on a ship, finding that the captain not unable to do this job, then you proceed to find another set of ship and captain. Why not just replace the captain?

Morarity

Just pointing out:

             L                  R
   ---------------------------------------
L  |      MOLALITY     |     MOLARITY    | 
   --------------------------------------- 
R  |      MORALITY     |     MORARITY?   |
   ---------------------------------------


Why hasn't someone filled the gap? Quick, quick, someone define 'morarity'!
(On an interesting note, MORARITY is an anagram of MORIARTY, the archenemy of Sherlock Holmes. Also, I would reckon a Japanese speaker of English would have a hard time distinguishing the four since romanisation of all four would be the same.)