I am currently reading Stuart Kauffman's "Reinventing the Sacred" and it's turning out to be one of the most thought-provoking books I have read in a long time, full of mind-bending ideas. Kauffman who was originally trained as a doctor was for many years a member of the famous Institute for Complexity in Santa Fe, which is a bastion of interdisciplinary research.
Kauffman is a kind of polymath who draws upon physics, chemistry, biology, computer science and economics to essentially argue the limitations of reductionism and the existence of emergent phenomena. He makes some fascinating arguments for instance about biology not being reducible to specific physics. One of the main reasons this cannot be done is because the evolution of complex biological systems is contingent and can follow any number of virtually infinite courses depending on slightly different conditions; according to Kauffman, this infinity is not just a ‘countable infinity’ but an ‘uncountable one’ (more on this mind-boggling distinction later). Biological systems are also highly non-linear and full of feedback and 'surprises' and these qualities make their prediction not just very difficult in practice but even in principle.
I am sure I will have much more to say about Kauffman’s book later, but for now I want to focus on his argument against reductionism based on what is called the ‘multiple platform’ framework. Kauffman’s basic thesis draws on an argument made by the Nobel laureate Philip Anderson. Anderson wrote a groundbreaking article in Science in 1972 extolling the limits of reductionism. To illustrate the multiple platform principle, he talked about computers processing 1s and 0s and manipulating them to give a myriad number of results. The question is: is the processing of 1s and 0s in a computer uniquely dependent upon the specific physics involved (which in this case would be quantum mechanics)? The answer may seem obvious but Anderson says that it’s hard to make this argument, since one can also get the same results from manipulating buckets that are either empty (0s) or filled with water (1s). Thus, the binary operations of a computer cannot be reduced to specific physics since they can be modeled by ‘multiple platforms’.
Another example that Kauffman cites is of the Navier-Stokes equations, the basic equations of fluid dynamics. The equations are classical and are derived from Newton’s laws. One would think that they would be ultimately reducible to the movements of individual particles of fluid and thus to quantum mechanics. Yet as of today, nobody has found a way to derive the Navier-Stokes equations from those of quantum mechanics. However, the physicist Leo Kadanoff has actually ‘derived’ these equations by using a rather simple ‘toy world’ of beads on a lattice. The movement of fluids and therefore the equations can be modeled by moving the beads around. Thus, we again have an example of multiple platforms leading to the same phenomenon, precluding the unique dependence of the phenomenon on a particular set of laws.
All this is extremely interesting, but I am not sure I follow Kauffman here. The toy world or the bucket brigades that Kadanoff and Anderson talk about are models. Models are very different from physical laws. Sure, there can be multiple models (or platforms) for deriving a given set of phenomena, but the existence of multiple models does not preclude dependence on a unique set of laws. A close analogy which I often think of is from molecular mechanics. A molecular mechanics model of a molecule assumes the molecule to be a classical set of balls and springs, with the electrons neglected. By any definition this is a ludicrously simple model that completely ignores quantum effects (or at least takes them into consideration implicitly by getting parameters from experiment). Yet, with the right parametrization, it works well-enough to be useful. There could conceivably be many other models which could give the same results. Yet nobody would make the argument that the behavior of molecules modeled in molecular mechanics is not reducible to quantum mechanics.
Kauffman’s argument that the explanatory arrows don’t always point downwards because one cannot always extrapolate upwards from lower-level phenomena is very well-taken. Emergent properties are surely real. But at least in the specific cases he considers, I am not sure that one can make an argument about phenomena not being reducible to specific physics simply because they can be derived from multiple platforms. The multiple platforms are models. The specific physics constitutes a set of laws, which is quite different.
The jewel of physics faces the 4% challenge
The size of the proton has shrunk by 4%, or so they tell us. The research which was published in Nature and has created waves apparently interrogated the proton with a much more reliable subatomic entity, the muon, which led to a more accurate result. The result of course testifies to the incredible power of modern science to divine such unbelievably small numbers.
But according to a NYT article, this might mean that the "jewel of physics", quantum electrodynamics, may be in trouble. QED which was developed by Richard Feynman and others is the most accurate theory known to science, and has calculated the magnetic moment of the proton to an accuracy of ten significant figures with respect to experiment. As Feynman himself said, this is like calculating the distance between New York and New Orleans to within the width of a hair.
The present measurement could shake up this success a bit according to the article:
Who said challenges do not abound in modern physics!
But according to a NYT article, this might mean that the "jewel of physics", quantum electrodynamics, may be in trouble. QED which was developed by Richard Feynman and others is the most accurate theory known to science, and has calculated the magnetic moment of the proton to an accuracy of ten significant figures with respect to experiment. As Feynman himself said, this is like calculating the distance between New York and New Orleans to within the width of a hair.
The present measurement could shake up this success a bit according to the article:
When that new radius, which is 10 times more precise than previous values, was used to calculate the Rydberg constant, a venerable parameter in atomic theory, the answer was 4 percent away from the traditionally assumed value. This means there are now two contradicting values of the Rydberg constant, Dr. Pohl explained, which means there is either something wrong with the theory, quantum electrodynamics, or the experiment.In other news, a physicist has postulated that gravity is not really a fundamental force but could be a manifestation of the second law of thermodynamics.
“They are completely stunned by this,” said Dr. Pohl of his colleagues. “They are working like mad. If there is a problem with quantum electrodynamics this will be an important step forward.”
The late Caltech physicist Richard Feynman called quantum electrodynamics “the jewel of physics,” and it has served as a template for other theories.
One possibility is that there is something physics doesn’t know yet about muons that throws off the calculations.
Or perhaps something we just don’t know about physics. In which case, Jeff Flowers of the National Physical Laboratory in Teddington in Britain pointed out in a commentary in Nature, a new phenomenon has been discovered not by the newest $10 billion collider but by a much older trick in the book, spectroscopy.
“So, if this experimental result holds up, it is an open door for a theorist to come up with the next theoretical leap and claim their Nobel Prize,” Dr. Flowers wrote.
Who said challenges do not abound in modern physics!
Computational modeling of GPCRs: What are the challenges?
GPCRs are extremely important proteins both for pure and applied science research, but they are also very difficult to crystallize and hence structural information on them has been sparse. Naturally in such a case, computational modeling can be expected to be of great value of providing insight into GPCR structure and function. However, even though progress has been impressive, such modeling still has to overcome many challenges. A recent review lists some of them.
Firstly, in the absence of crystal structure, homology modeling wherein a sequence for an unknown structure is 'threaded' through that of a known one is well-established as a valuable technique. However the technique is tricky. First and foremost one has to get the right sequence alignment between the target and the template. As the article notes, recent studies have suggested that using multiple structures for alignment instead of a single one provides better results. Particularly noteworthy is this detailed study. Once a homology model has been obtained, it must be meticulously examined, both for internal consistency (bad contacts, incorrect hydrogen bonding interactions etc.) and for its agreement with experiment. Data from cross-linking studies and mutagenesis can be used to achieve this. A recent promising development has been termed 'ligand-supported homology modeling'. In this process, topographical protein-ligand interaction data from mutagenesis and other studies is used to limit the number of homology models. Such data-driven homology modeling is becoming increasingly popular.
Once a good homology model has been obtained, many things can be done with it. Molecular dynamics (MD) simulations provide a very valuable avenue for exploring protein motion and be used to detect structural features not obvious in static models. A recent MD simulation of the beta-adrenergic receptor helped to resolve discrepancies between biochemical and structural observations. MD simulations can be used to investigate protein dynamics and to refine the models. Several challenges present themselves during this procedure. Firstly, while helices in GPCRs can be well-modeled, loops (of which there are six- three intracellular and three extracellular) are much harder to model because of their higher flexibility and because they are often ill-resolved in crystal structures. Unfortunately, it's these loops which are important ligand-interacting elements, so getting them right is key. Recently developed algorithms for loop-refinement based on either first-principles energy minimization or by statistical modeling based on a database of known loop conformations have been used in getting loops right. Also, state-of-the-art long MD simulations spanning several microseconds can be used to model large-scale structural changes in GPCRs.
There are still immense challenges still to be overcome in understanding GPCRs. One of the biggest concerns the cycling between several inactive and active states (and not just one active and one inactive state) that present often conflicting features that can be subject to varying interpretation. For instance, for class A GPCRs (which is the largest class), it has been well-established that activated states involve the breakage of the "ionic lock", a salt bridge between arginines and glutamates on transmembrane helices 6 and 3. Breaking this lock allows TM6 to shift away from TM3 and towards TM5, a hallmark of GPCR activation. Yet the MD study on the beta2 cited above indicated that even an inactive state may feature breakage of this lock.
In the GPCR jungle, strange shape-shifting creatures appear and clutch gems of insight in their palms. It is only fitting that we throw the kitchen sink at them to unravel their secrets, and computational techniques can only be a valuable arrow in this quiver.
Yarnitzky T, Levit A, & Niv MY (2010). Homology modeling of G-protein-coupled receptors with X-ray structures on the rise. Current opinion in drug discovery & development, 13 (3), 317-25 PMID: 20443165
Lindau 2010: Island Full of Ideas
I am very fortunate in being invited again to blog for the 60th Meeting of Nobel Laureates in Lindau, Germany. This year's interdisciplinary star-cast features more than 60 Nobel Prize winners from physics, chemistry and medicine and more than 600 young students and researchers from around the world. It's been a pleasure blogging for this one-of-a-kind meeting. Below are listed some of my posts with excerpts. You can click on the titles to read the full posts.
1. Reflections on Nobel City
Cities, just like human beings, have character. The character is frequently defined by little things as well as big. For instance New York is The Big Apple, Paris the city of fashion, Sydney the city with the Opera House and Rio de Janeiro the carnival city. Small cities are also known for their own accomplishments. For instance, last year I visited the the little German city of Magdeburg which is known for Otto von Guericke, the man who established the physics of vacuums through a famous experiment involving horses...
2. Microwaves, Magnetism and Machine Grease: A Paean to Tool-Driven Science
John Turton Randall was trying hard, real hard. For some time now, the University of Birmingham physicist was focusing on trying to improve the features of a machine which transmitted and received electromagnetic waves. A few years back this would have been just another intriguing academic problem for a physicist to crack, but this time it was a matter of life and death for thousands. Literally. It was 1939, and an ominous menace loomed large over Europe in the person of Adolf Hitler. The machine Randall was working on was designed to thwart Hitler's attempts to invade the British mainland. It sent out electromagnetic waves of meter wavelength and tried to deduce the position of an object based on its reflection of these waves. The operating principle of this humble machine later turned into a household name- Radar...
3. Pigeon Waste, Cosmic Melodies and Noise in Scientific Communication
There it was, that darned noise again.
Nobody could possibly be happy cleaning pigeon droppings. Yet Arno Penzias and Robert Wilson were being forced to do it. As good scientists they simply could not avoid it, since they had to discount the role of this "white dielectric substance" in the noise that was plaguing their equipment. When they finished with the cleaning and dispatched the pigeons by mail to a faraway place, the noise still did not disappear. And it seemed to come from all directions. The implications of this annoying constant background hum, corresponding to a temperature of only 3 degrees above absolute zero, signified one of the most momentous discoveries in twentieth-century physics, notable even among Nobel Prize-winning discoveries...
4. Paul Crutzen's Other Big Idea
Nobel Laureate Paul Crutzen will be at Lindau this year, along with his fellow recipient F. Sherwood Rowland. The two along with Mario Molina contributed to one of the most significant intersections of science with politics and public policy in the twentieth century when they discovered the effects of chlorofluorocarbons and other chemical compounds on the all-important ozone layer. Crutzen is well-known for that contribution...
5. Mountains Beyond Mountains
The scientist, by the very nature of his commitment, creates more and more questions, never fewer. Indeed, the measure of our intellectual maturity is our capacity to feel less and less satisfied with our answers to better problems.- G.W. Allport, Becoming, 1955
Science in the popular mind consists of a series of "Eureka!" moments. Such moments are supposed to suddenly propel scientific fields ahead at accelerating rates. Many anecdotes from scientific history seem to confirm this belief. It all begins with Archimedes jumping out of the bath after discovering the principle of buoyancy. Other examples include the apple falling on Isaac Newton’s head, August Kekule waking up from a dream and realizing the structure of benzene, Enrico Fermi discovering slow neutrons by ‘randomly’ substituting a block of paraffin for a tabletop, Alexander Fleming ‘accidentally’ discovering the action of a famous mold on bacteria, and Werner Heisenberg discovering the awesome structure of the quantum world after an all-night session on the island of Heligoland in the North Sea...
6. Heisenberg and Dirac
Beatrice's story about Heisenberg possibly inspiring the "Schunkelwalzer" dancing tradition at Lindau reminds me of an ancedote about Heisenberg and Paul Dirac. Both were two of the most accomplished scientists of the twentieth century who made foundational contributions to quantum mechanics. But while Heisenberg loved song, dance and wine, Dirac was a very quiet man and a singularly unusual character who generously extended his abstract thinking to interpreting the world literally. This inevitably led him to being an anecdote generator throughout his life and many stories about him abound. Here are a few, concluding with the story about him and Heisenberg...
7. Infections and Disease: The Golden Age
Harald zur Hausen's discovery of the link between infection and cancer provides a window into what may turn out to be one of the most fascinating lines of inquiry in twenty-first century medical research: the link between microorganisms and what have been traditionally considered chronic diseases.
This line of inquiry is founded on an evolutionary truth. Bacteria and viruses have been human beings' most constant companions, existing on this planet billions of years before we did and greeting us as we climbed out of the trees and walked out of Africa. Since the very beginning we have been engaged in an arms race with microbes. The conventional wisdom is that these arms races have led to an essentially benign co-existence between us and "them". But recent thinking has challenged this widespread belief and the truth appears to be more complicated...
1. Reflections on Nobel City
Cities, just like human beings, have character. The character is frequently defined by little things as well as big. For instance New York is The Big Apple, Paris the city of fashion, Sydney the city with the Opera House and Rio de Janeiro the carnival city. Small cities are also known for their own accomplishments. For instance, last year I visited the the little German city of Magdeburg which is known for Otto von Guericke, the man who established the physics of vacuums through a famous experiment involving horses...
2. Microwaves, Magnetism and Machine Grease: A Paean to Tool-Driven Science
John Turton Randall was trying hard, real hard. For some time now, the University of Birmingham physicist was focusing on trying to improve the features of a machine which transmitted and received electromagnetic waves. A few years back this would have been just another intriguing academic problem for a physicist to crack, but this time it was a matter of life and death for thousands. Literally. It was 1939, and an ominous menace loomed large over Europe in the person of Adolf Hitler. The machine Randall was working on was designed to thwart Hitler's attempts to invade the British mainland. It sent out electromagnetic waves of meter wavelength and tried to deduce the position of an object based on its reflection of these waves. The operating principle of this humble machine later turned into a household name- Radar...
3. Pigeon Waste, Cosmic Melodies and Noise in Scientific Communication
There it was, that darned noise again.
Nobody could possibly be happy cleaning pigeon droppings. Yet Arno Penzias and Robert Wilson were being forced to do it. As good scientists they simply could not avoid it, since they had to discount the role of this "white dielectric substance" in the noise that was plaguing their equipment. When they finished with the cleaning and dispatched the pigeons by mail to a faraway place, the noise still did not disappear. And it seemed to come from all directions. The implications of this annoying constant background hum, corresponding to a temperature of only 3 degrees above absolute zero, signified one of the most momentous discoveries in twentieth-century physics, notable even among Nobel Prize-winning discoveries...
4. Paul Crutzen's Other Big Idea
Nobel Laureate Paul Crutzen will be at Lindau this year, along with his fellow recipient F. Sherwood Rowland. The two along with Mario Molina contributed to one of the most significant intersections of science with politics and public policy in the twentieth century when they discovered the effects of chlorofluorocarbons and other chemical compounds on the all-important ozone layer. Crutzen is well-known for that contribution...
5. Mountains Beyond Mountains
The scientist, by the very nature of his commitment, creates more and more questions, never fewer. Indeed, the measure of our intellectual maturity is our capacity to feel less and less satisfied with our answers to better problems.- G.W. Allport, Becoming, 1955
Science in the popular mind consists of a series of "Eureka!" moments. Such moments are supposed to suddenly propel scientific fields ahead at accelerating rates. Many anecdotes from scientific history seem to confirm this belief. It all begins with Archimedes jumping out of the bath after discovering the principle of buoyancy. Other examples include the apple falling on Isaac Newton’s head, August Kekule waking up from a dream and realizing the structure of benzene, Enrico Fermi discovering slow neutrons by ‘randomly’ substituting a block of paraffin for a tabletop, Alexander Fleming ‘accidentally’ discovering the action of a famous mold on bacteria, and Werner Heisenberg discovering the awesome structure of the quantum world after an all-night session on the island of Heligoland in the North Sea...
6. Heisenberg and Dirac
Beatrice's story about Heisenberg possibly inspiring the "Schunkelwalzer" dancing tradition at Lindau reminds me of an ancedote about Heisenberg and Paul Dirac. Both were two of the most accomplished scientists of the twentieth century who made foundational contributions to quantum mechanics. But while Heisenberg loved song, dance and wine, Dirac was a very quiet man and a singularly unusual character who generously extended his abstract thinking to interpreting the world literally. This inevitably led him to being an anecdote generator throughout his life and many stories about him abound. Here are a few, concluding with the story about him and Heisenberg...
7. Infections and Disease: The Golden Age
Harald zur Hausen's discovery of the link between infection and cancer provides a window into what may turn out to be one of the most fascinating lines of inquiry in twenty-first century medical research: the link between microorganisms and what have been traditionally considered chronic diseases.
This line of inquiry is founded on an evolutionary truth. Bacteria and viruses have been human beings' most constant companions, existing on this planet billions of years before we did and greeting us as we climbed out of the trees and walked out of Africa. Since the very beginning we have been engaged in an arms race with microbes. The conventional wisdom is that these arms races have led to an essentially benign co-existence between us and "them". But recent thinking has challenged this widespread belief and the truth appears to be more complicated...