Scientific curiosity

From birds and fish to cells [*]

2008-02-24T17:28:00.000-08:00

A physicist’s view of collective transport in biological systems

Let me motivate what I want to say today with a couple of videos. First up, an amateur video of a flock of starlings in Scotland.

Or see this one, where the flock cohesively responds to a predator. A Starling is a small bird, shown in the picture alongside, about the size and shape of a “myna” if you are familiar with it. They fly in flocks that do amazing things as a collective entity as you just saw in the above example. Understanding how they do this is field of active research as indicated by this cover of the October issue of Physics Today. I will tell you a little bit about how they do that subsequently. But you might say to me, “They are birds, and they have brains, albeit “bird brains”, so they see, process that information somehow and do stuff. Why would a physicist concern herself with that?” So, to make my point even more clear, let me show you one more video.

This one is a microscopic movie of a bacterial swarm (obtained from here). Do you see the complex flow patterns they exhibit? These guys clearly do not have brains. It might be that this rich collective behavior originates in more chemistry than physics, but clearly not biology. And to make my point that it is indeed just physics, I ask you to look at this other video (obtained from here)

Do you see the similarity in the flow pattern to that seen in the bacteria? Can you guess what you are looking at? It is just a vibrated monolayer of some centimeter long metal rods! Whatever is going on here is clearly just physics. Moreover, one can mathematically represent the motion of the bacteria/birds and those of the rods by the same set of equations! What I want to do in the rest of this post is to give you a flavor of some of the physics behind these and other collective phenomena in biological systems.

When looking at fish schools or bird flocks, the first postulate that comes to mind is that the phenomenon is “follow the leader”, with one bird/fish doing its own thing, and the others following. But as stated above, the things that birds/fish do is “mathematically similar” to what the bacteria do. So “follow the leader” seems an unlikely scenario. The logical next question to ask would be, “What are the minimal rules that can give rise to this kind of behavior?” We have known the answer to this question for a while now [1]. The rules are the following – Each member of the flock does each of three things a) Alignment : Adjust my direction of motion so that I am going in the same direction as my neighbors, b) Velocity matching : I adjust my speed so that I am going with the same speed as my neighbors c) Cohesion : I try to keep the distance from my neighbors the same at all times. With these basic rules and simple boundary conditions for entities at the edge of the flock, like “If there is food, turn towards it” and “If there is danger, turn away from it”, most of the complex patterns exhibited by these groups of organisms can be reproduced!

But these are just rules. So, the next question to ask would be, “Can these rules come about from just physical interactions?” Let us ignore the boundary conditions associated with food/predator for the moment, they clearly are chemistry and other higher processes and focus on the bulk flocking rules. What is a unifying thing between the birds, the fish the bacteria and so on? What they are, are objects that have a non-spherical shape that actively move through a medium (air/water etc.). Now what does that mean? They exert a force on the medium [2]. The medium responds, i.e., the fact that my bird/fish/bacterium is pushing on the fluid induces a flow in the fluid itself. This response now propagates through the fluid. So, a bird/fish/bacterium that is elsewhere will feel this change in the fluid, in terms of the local flow field and pressure gradients. And it will adjust its own force on the fluid accordingly, and this whole things feeds back to the other entities in the flock. This phenomenon is called hydrodynamic interaction. And this is the dominant interaction that produces the three aspects of flocks that is listed in the previous paragraph!

Further, I want to make the case that this quest for minimal mechanisms for collective behavior is not just restricted to animal group behavior on the different scales encompassed from birds to bacteria. For this, see the famous video below.

This is a video of a neutrophil chasing a bacterium and then gobbling it, the immune system of your body at work. I know what you are thinking, “This is one cell chasing one bacterium and the primary thing at play here is chemotaxis, so what is collective about this?” The collective aspect lies in how the cell crawls, i.e., at the sub-cellular scale. The interplay between membrane fluctuations, the stresses in the actin-microtubule network that makes up the cytoskeleton of the cell, the interaction of this network stress with the medium that the cell is in and many other things go into understanding how the cell crawls. The mathematical paradigm and the physics aspects of this question are not so different from those one uses to address animal group behavior we considered earlier! But for now, this is just a teaser. A separate post on this to follow later.

[*] Cross posted from my personal blog, where this really belongs. Will write a really SC post in a couple of weeks

[1] Actually the first instance in literature was in the context of an algorithm for computer graphics, available here.

[2] If we want to be careful, then clearly third law tells us that the swimmer must at least be a force dipole. Since there is no mathematics displayed here, I fudge this point.

On Rubber Bands, Entropic Springs and Elastomers

2007-12-08T09:28:00.001-08:00

Let us begin by doing a Gedanken experiment. Or you could literally do it if you have the ingredients. Imagine a ring made of some thin wire or may be a regular piece of string. And now imagine stretching it between you fingers. What would happen? It would just become stiff and you cannot do much more. Now imagine doing the same experiment with a rubber band. You will be able to extend the rubber band to at least a few times its original size. And if you let it go, it goes right back to its original shape and size. So, the experiment shows me that rubbery materials can be “deformed reversibly” to many times their original size. This post tries to tell you how and why. Also, in the concluding paragraph, the context of such considerations as applicable to biological systems is mentioned (feel free to skip the section named theory, the rest is sufficient story by itself).

Microscopics of a regular solid

As our starting point, let us consider the elasticity of a regular material, the string or the metal wire in our earlier experiment. What is elasticity anyway? It is the theory that tells you how much force you need to exert in order to deform/extend a material by a given amount. Let us simplify even further. Let us consider a spring attached to a wall and pulling on it. How much force do I need to exert to do this? This is given by the “Hooke’s law” that we all know and love. Let F be the force and x be the extension of the spring from its rest length. Then F=-kx is the statement of Hooke’s law, i.e., the amount of force I need to exert grows linearly with the extension. And the force law is characterized by a single constant, the spring constant of the particular spring I am using.

Now, why did we start there? The reason is that you can get a reasonable theory for the elasticity of a solid if you considered it to be made up of atoms connected by springs (see picture along side), whose spring constants are determined by the electromagnetic interaction among the atoms [1]. What is the typical energy scale of this spring like interaction, i.e., how stiff are these springs? It is about a few electron volts typically, which makes them really stiff springs (but for us to realize that the spring is really stiff, I need to compare this energy scale to something else right? We will come back to this later).

Microscopics of rubber

Note that the picture above is how a string or a wire looks like in the microscopic scale. Next let us ask what does a rubber band look like? [2] It looks like the picture along side. A rubbery material is made of coiled up flexible polymers that are “crosslinked” by some chemical agents (the big black dots in my picture) [3]. For clarity I have caricatured the three polymers shown in the picture with different colors. The message here is that the polymers are in some coiled state. When I stretch such a material, what I am doing is pulling the black dots apart. What will this do to a polymer? It will uncoil it some. You already know that uncoiling a string costs much less energy than trying to pull at a fully extended string in an attempt to lengthen it. This is primarily the difference between rubbery materials and regular crystalline solid. These kinds of solids, to which class the rubber band belongs, have a special name, they are called “elastomers”. Note that I can say that I understand the elasticity of rubber-like materials, if I can get the equivalent of “Hooke’s law” for this system. And for this purpose I need to understand what happens when I pull on a polymer. In the rest of this post, we will try to explain how to describe this theoretically.

The theory

Before we proceed with the theory, let us pause for a moment. How can what I said above be right? If I had a string coiled up on my table and I pull it open to its full length, it does not cost me any energy at all. It comes apart nice and easy. If I were to take the analogy above seriously, the rubber band should not offer me any resistance at all. Pulling at a rubber band must be like pulling on water, it should just come apart. But this is clearly not true. So what did I miss? What I missed is called “entropy”. Suppose my rubber band is at zero temperature (no no, not 0C or 0F but 0K). Then the analogy with the macroscopic string holds and the rubber band should indeed flow like water till the polymers are completely extended. But at all finite temperature, the polymers in rubber are jiggling around with some kinetic energy. And that makes all the difference as we will try to show below.

In order to quantify this notion we need to ask what makes physical systems happy (some of these notions are developed in a slightly different context in this post). Let us consider a regular spring again. If we just let the spring be, it has a characteristic length, let us call this the rest length of the spring. This is the length in which the spring is happiest. Now I pull on the ends of the string. I have to do some work to pull it because I am moving the spring away from the state it is happiest in. This work gets stored in the spring as potential energy. Alright, now let us ask at finite temperatures what is the state in which the polymer is happiest? It is happiest when it has the largest entropy.

What is this entropy? For a polymer, we can understand it as follows. Now suppose you have a coiled up string. It looks like a disc right? The size of this disk is called the “radius of gyration” of the polymer (a measure of the lateral extension of the polymer). Suppose the length of the polymer is L. I ask you, “how many ways can you make an object of length L with it?”, you will tell me, “Exactly one way, stretch the polymer out to its full length”. Similarly, if I wanted to make an object of some length A which is much much smaller than L, again we can do this in exactly one way, namely make a tight coil out of the polymer with each turn of the coil having a radius A. But, if I wanted some intermediate sized object, then I can make it in many many ways, in each of these ways, the polymer will be coiled in a slightly different way. The entropy of a polymer of radius of gyration R is the number of different configurations the polymer can have given this radius as its lateral dimensions. As stated earlier, the polymer wants to have maximum entropy. Hence, from the arguments above it does not want to be fully extended or tightly coiled, but rather be coiled up in some intermediate state. This intermediate state has a size equal to the square root of its length L [4].

So in my unstretched rubber band, I have polymer coils that are happy, i.e., in the state of maximum entropy. Now I pull on the rubber band. What happens? I stretch the polymers. Their radius of gyration increases above the optimal value, their entropy goes down and they are unhappy. So, just like you pay an energy cost to stretch a normal spring, you pay an entropy cost to stretch a polymer. If you calculate this cost, you can derive the equivalent of Hooke’s law for these polymers [5]. Then you find that if I stretch a polymer by an amount x, then the force I need to apply is F=(CT/L)x, where C is just a constant, and T is the temperature of the system. So, a polymer behaves like a spring with a spring constant determined by the temperature of the system! And the reason it behaves like a spring is because of a loss in entropy rather than a gain in energy. This is what people call an “entropic spring”. Now, suppose I compare this spring constant with the spring constant associated with atomic solids we considered earlier, I find that it is 0.00001 times smaller! Thus polymers form very loose springs. And rubber is exactly like a regular solid but with a really itty-bitty spring constant that scales with the temperature of the solid [6].

Conclusion

In summary, rubbers are solids made by crosslinking polymers. Polymers form entropic springs whose stiffness increase as the temperature increases. And this explains why rubber bands become brittle and break when you try to stretch them on hot summer days! But at the start of the post, I said that such considerations are biologically relevant. How is that? The cell wall is a rubber! It is a crosslinked polymer mesh made of polymers that are called actins and microtubules. You will now say to me, why would I want to know about the elasticity of a cell wall? The reason is that it is the elasticity of the cell wall that allows a cell (those that are not swimmers that is) to crawl. And all questions associated with the motility of such cells boils down to understanding the elasticity of the cell wall. And you need to start by understanding the elasticity of the plain old rubber band first!

Jargon, Caveats and Disclaimers

[1] Coulumb, screened coulomb, Lennard-Jones, you take your pick.

[2] I am fudging scales here, mapping Angstroms to a fraction of a micrometer, but for simplicity we ignore this difference here.

[3] This process is called vulcanization, that turns a complex fluid into a solid, gives it a finite zero frequency shear modulus.

[4] You can see this easily if you think of the polymer as a 3D random walk of length L. Then the RMS distance the walker would travel is Square root of L right?

[5] For the experts, note that you can derive this readily. Take a Boltzmann definition for the entropy as S=k_BLogW, where W is the number of configurations of a polymer of radius of gyration R. Using the random walk analogy earlier, this is W=exp(-R^2/L). So the loss in entropy due to stretching must be S(R)-S(R+x). And force F=-T(dS/dx)x (just a standard response relation).

[6] You should ask me now how come I ignored entropy when considering elasticity of an atomic solid. The fact is that entropy strain independent for harmonic solids and plays no role in the elasticity (a brief note on this is here).

A layman’s tutorial to the dark side II

2007-11-20T13:19:00.000-08:00

In the previous post, we tried to answer the question “What is dark matter?” In this post, in the same reductionist spirit, we try to answer the question “What is dark energy?” [1]. For a number of years, I kept thinking that dark energy was just “E =mc^2” type energy associated with dark matter. It was only in my second year in grad school that I realized how hopelessly wrong I was.

As in the context of dark matter, dark energy is postulated to exist to solve some problems associated with explaining observed phenomena. So, first let us talk about what the problem is. The problem is that the universe is expanding and the rate of this expansion is increasing, i.e., the expansion of the universe is accelerating! The first question you might ask is “Are you sure?” or “How do we know this?” I do not want to discuss red shifts and the Hubble constant here. So I refer you to wikipedia for more info on this. What I would like to do here is to take as a given that the universe is expanding and accelerating and ask how can we understand this?

The theory of classical gravity is General Relativity. A layman’s minimal picture of what GR is with respect to the familiar Newtonian picture can be summarized quickly enough [2]. But, for the purpose at hand, it suffices to say that one of the consequences of GR is that matter and energy exert a pressure on space time much like a gas in a chamber exerts a pressure on the piston [3]. Now, suppose we use this piston analogy for minute. If I have gas under pressure, kept that way by putting a weight on the piston. I suddenly remove this weight and I ask you what you expect the motion of the piston to be like. You would tell me that the piston would first instantaneously accelerate to a large speed, then decelerate slowly as the gas in the chamber expands. Yes? This same picture is what you would expect to apply to the universe as well. You can think of the total mass and energy of the universe as N in some units. Suppose the volume of space time is V(t) at a given time t, then the pressure exerted by this mass and energy will be proportional to N/V. At the time of the big bang, i.e., t=0, this was enclosed in a very very small volume. Hence it must have exerted tremendous pressure and the universe must have expanded rapidly. As time increases, universe expands, V increases, N/V(t) decreases, and so the universe should expand more slowly than before. If this was the case, then there would be no problems and we would not have so many cosmologists so worried so much of the time.

But, observations of far away galaxies tell us that the universe is expanding faster than it was at earlier times! The question is, how can this be? Clearly, it cannot be from the regular mass and energy that we talked about earlier. So we have to think of something else. One of the possible “something else” is that there is an (as yet mysterious) energy associated with space time itself. If this was the case, then as the universe expands, the number of space time points increases in some sense. Then, this intrinsic energy associated with the space time points increases as well and so the pressure builds up and the universe expands faster. So, the existence of such an energy, the dark energy, could be one possible explanation for the accelerating universe. But where the heck does this energy come from? We have no clue at the present time. Hence the name dark energy.

[1] A more complete and erudite discussion is here.

[2] This is fishing. If you ask me, I will tell you kind of thing.

[3] I know that relativist cringe at such statements, but I do not see how else to say this simply.

A layman’s tutorial to the dark side I

2007-11-16T15:18:00.000-08:00

I am a condensed matter theorist. So, I know next to nothing about gravity or cosmology. But, this week, I attended a few Cosmology seminars and hence was motivated to write this post, which is intended to be a layman’s answer to the following question: WTF is dark matter and dark energy? I have been meaning to do this for a while, just because of all the press these things get, for example this old article on dark energy in NYT that was featured along with the cosmologist involved on David Letterman. There is even a movie by this name. This Friday evening is the time to get it off my chest! [1]

Alright. First let us begin with dark matter in this post, which in many ways is the simpler issue. There is all kinds of evidence that all the matter we see in the universe is not all there is. What is some of this “evidence”? Let me try and give you a couple of examples. One of them is associated with “galactic gravitational potentials”. What does that mean? Now, suppose I was observing a galaxy in my telescope. I saw a star that was far from the central bright core of the galaxy. Then, I expect that the star will have a velocity (GM/R)^1/2, where R the distance of the star from the center and M is the mass of the bright stuff in the middle [2]. Now I measure the velocity of this star, it is moving much faster than this estimate. You might say “Aha! You are just underestimating the mass of the bright object in the middle!” But, if you believe that the universe is homogeneous (same everywhere) and isotropic (same in every direction you look), you have no choice but to conclude that there is just some universal parameter that you have to fit observed data, called the “Mass to light” ratio (and you have no choice but to believe this hypothesis unless you want to also believe that the earth is the center of the universe somehow). And I urge you to go and play with this applet to see that you CANNOT fit the observed curve with just one such parameter. So, there must be something else. What that something else could be is some mass that I cannot see, that I don’t know anything about so far, such that the star that I think is far away from most of the mass in the galaxy is not so far at all, for this stuff I cannot see is filling the intermediate space that appears to me to be empty. So, the postulation of the existence of this “dark matter” is one possible explanation for these weird velocities of apparently far-flung stars in galaxies.

One more piece of evidence is associated with the mass of clusters of galaxies. This is rather involved, but if you want, you can go read about it in this post on Cosmic Variance [3]. So, let me move on to another piece of evidence. This is associated with large scale structure in the universe (this is just jargon for stars, galaxies, you and me). The way this argument works is as follows. We know how the universe is today. We use our telescopes, optical or otherwise and know the mass density in the universe everywhere. We also know what the mass density in the universe was when it was only 400000 years old (that is very young on cosmological time scales). This info comes from the cosmic microwave background [4]. Then knowing the mass in the universe, and knowing the laws of gravity, I should be able to go from the scenario 400000 years ago to now. But, I cannot. It turns out that if I try to so this, I get a mass inhomogeneity much smaller than what we have today, to the extent that you and I cannot be here. But we are here. So, one possible explanation could be that there is this “dark matter” we invented earlier is there in the early universe and the information about its distribution is not in the cosmic microwave background and hence we are not able to get to the present structure of the universe and the fact that you and me are here.

Do you see? The postulation of this “dark matter” solves many problems that are around in astrophysics and cosmology. But, the problem is that we don’t know yet what this “dark matter” made of and how it talks to the regular matter that you and I are made of. We have ideas as theorists and we have experimentalist out there testing to see if any of these ideas hold water. But until then, we just have to live with “dark matter”! [5]

[1] There are a whole bunch of erudite articles on the web, for example, this one by Sean Carroll. I will try to be very minimal here, no way near as erudite.

[2] You can do an itty-bitty circular motion calculation to see this, given that gravity leads to acceleration GM/(R^2) on a particle at a distance R.

[3] There is also an interesting comment thread here that is a back and forth on dark matter, that we (readers and writers) at scientific curiosity will do well to emulate! :)

[4] This cosmic microwave background comes from an event in the past of our universe that is called decoupling. But I have to do a lot more work to get this point across. I will provide an update with some appropriate reference subsequently.

[5] But this, namely the postulation of the existence of dark matter is not the only way out of the many problems that cosmologists face. But the other ways out are deferred to a subsequent post coming up shortly, so stay tuned.

Classification of Protein Structure

2007-08-09T20:14:00.000-07:00

Structures of proteins: In all modern day organisms, proteins play a wide variety of roles in the cell. At the molecular level, they are responsible for performing all the mechanical work done by your muscles (as known until now) in addition to the chemical catalysis that they perform on nearly all biochemical reactions inside the cell [1]. The immediate question that begs to be answered "How are these complex molecules able to perform this work? How are they so specific in what they do and specific to the reactions that they catalyze?" While the answer to these questions are nontrivial and the subject of research of more than half the biophysics labs world wide, the common theory going around in the scientific world is that the function of a protein is determined by its structure [2]. This statement is only partially accurate and the reasoning behind this statement is that a protein functions because it is able to have a certain 3-dimensional configuration of certain atoms or functional groups in the amino acids that make up the active site of the protein and these functional groups are then able to catalyze the reaction. The specificity of the reaction they catalyze comes from the specific 3-dimensional configuration of these functional group that it is able to catalyze only when the substrate is able to interact with it in a certain manner. While it is true that the structure does determine how a protein will go about performing its function, these structures are static pictures of the molecule which is otherwise in motion [3]. In addition to the global motion of the molecule, there are relative motions of the atoms that make up the protein which leads to slightly different configurations of the important functional groups and hence they are neither completely specific nor is the function completely dependent on its structure alone.

Classification of Protein Structure: The average protein consists of about 20000-30000 atoms and in order to make sense of the structure of the protein, it is necessary to simplify the protein structure. There are more than 30000 structures in the protein database [4] and to go about looking at each structure would be horrendous. Hence, one needs to come up with a classification scheme for protein structure.

One way of simplifying it is to break it into parts called the secondary structure of the protein. There are various courses/books [1,2] to explain the secondary structure, but for our discussion, it is sufficient to know that certain configurations called alpha helices and beta sheets are common structural motifs found in nearly all proteins. While these secondary structures do help in understanding the local structure of the proteins, they give very little insight about the chemistry that the protein is able to perform and about it's active site itself.

A second and more meaningful attempt at classification of protein structure would be to find certain common structural motifs that can exist independently and classify the proteins based on these structural motifs. For example, a protein can be multifunctional but each function can be carried out independently by different parts of the protein even if you split them up. It could make sense that one can split these multifunctional proteins up based on what function they perform and if you can find the same structure/function motif in different proteins, club them together as a single group. In a protein, the part of the protein that can maintain its structure and function independently is called a domain [5]. Quite often domains of one shape combine with domains of very different shapes to form quite different proteins (very much like building blocks can come together in various different configurations giving walls of various different shapes) [6].

To give meaning to the classification scheme, it would also help to know which proteins perform related function (for example, perform the same reaction on different substrates) or have active sites in the same region of the protein structure. In order to give meaning to this classification, it is better to form groups of more closely related structures that perform similarly. Great minds have always argued that evolution should be the guiding principle while studying biology and it does make sense to classify proteins which have a common evolutionary origin from those that have achieved the same structure independently (also called convergent evolution).

There are various different databases that divide proteins into individual domains and divide these domains up into evolutionarily related groups heirarchically. These databases include the SCOP (Structural Classification Of Proteins) [7](manually divided), CATH (Class,Architecture, Topology, and Homologous superfamily) [8], and FSSP (Families of Structuraly Similar Proteins) databases [9](automatically performed). However, these databases are often flawed and corrections to these databases are often suggested in literature. Part of the problem is it is very difficult to say when similarity in structures occured due to homology (evolutionarily related), or convergence (evolutionarily independent origins). The trivial relationships are those that are apparent in the sequences of the two proteins. When two proteins have very similar sequences (measured by the number of times they have the same amino acid or a slightly related amino acid in the same position of the structure), they are related and statistics based on extreme value distributions can be used to find the probability of both proteins having a common origin [11]. However, the structure remains conserved (does not vary much) much more than sequences and below a certain sequence identity, it is very difficult to prove that there is a relationship between the two proteins without a structure [10].

Other problems that come up are related to the process by which structures are obtained (X-ray crystallography or NMR spectroscopy). These methods are inherently noisy because of various problems such as Heisenberg's uncertainty principle onto the crystallization conditions and the substrates that interact with the protein. So there is never a completely correct structural alignment (that is finding one to one which residues in the structure overlap each other) that also causes minor problems in the classification procedure.

But the most important problem is the level at which to classify structures. While domains are the most commonly used level of classification (because a domain is basically independent), during the evolution process, domains might not have been the basic level at which proteins were constructed. Rather subdomain level small structural units called structural words [12] or foldons [13] (because they could be independent folding units) could also be the smallest level of proteins that had evolved from the RNA world. The theory is that these foldons could come together and form various different domains and then evolved further to form proteins with different functions.

References:
[1] - Biochemistry by Stryer.
[2] - Introduction to Protein Structure by Branden and Tooze.
[3] - A perspective on enzyme catalysis by Stephen Bankovic and Sharon Hammes-Schiffer
[4] - RCSB protein database.
[5] - Domains.
[6] - Multi-domain protein families and domain pairs: comparison with known structures and a random model of domain recombination by Gordana Apic, Wolfgang Huber & Sarah A. Teichmann.
[7] - SCOP.
[8] - CATH.
[9] - FSSP.
[10] - How far divergent evolution goes in proteins - Murzin.
[11] - Maximum Likelihood Fitting of Extreme Value Distributions - Eddy..
[12] - On the evolution of protein folds - Lupas, Ponting, and Russell.
[13] - Foldons, Protein Structural Modules, and Exons by Anna Panchenko, Z. Luthey-Schulten, and P.G. Wolynes.

About Rainbows

2007-08-08T05:59:00.000-07:00

In this post, what I would like to do is illustrate scientific methodology and scientific curiosity in the context of the simple natural phenomenon called rainbows that we are all familiar with. The choice of this system is only because we all think we understand it and the physics involved is simple ray optics that we all learnt in school at some point (and of course it is pretty as in the picture along side). Now, the first step in scientific methodology is the collection and categorization of facts that we want an explanation for. In the context of rainbows, I want to be able to explain the following facts that I have established by watching rainbows in the sky. Apart from the obvious one about the colors, they are

1. Rainbows are seen when there is sun and rain (incipient or actual). That is why it is called a rainbow.

2. When I stand facing the rainbow, the sun is always behind me. I never see a rainbow on the same side of the sky as the sun.

3. The rainbow is a bow.

The next step is to look into my knowledge bank from the past and see what I already know that would be useful for me to explain the above facts. And I have to do this piece by piece. Now, I remember something about seeing dispersion, the breaking up of white light into its constituent colors when the light moves from one medium to another. Water glass held appropriately in bright sunlight, prisms I played with when I was young and so on. Yes? So, I begin my quest to understand a rainbow by quantifying this vague notion in my head [1].

Willebrord Snellius and the one and only Rene Descartes figured this out for us 400 years ago. They found that if a monochromatic (just jargon for one-color) light ray is incident on the interface between two media (say air and water), then light is refracted (jargon for “bent”) so that if the angle that the incoming ray makes with the interface is u_i , then the outgoing ray comes out at an angle [4] u_r = sin^-1((n1/n2)sin(u_i)), where n1 and n2 are properties of the two media in question called the refractive index of the material (again it is just a name, I could have called the property Karthik or Pradeep, but for the sake of conformity I call it by the name already given to it). Don’t worry about the formula if it looks complicated to you. Think of it as follows. If someone told you that they shined light at the interface of two media of given refractive indices, you can just tap some keys on your calculator and know where to put your eye or your camera so that you can see the refracted ray. So much for that. But how does this explain dispersion? The key is that the properties n1 and n2 depend not only on what the medium in question is (i.e., water, air glass etc) but also on the color of the light in question. Different colors will have different values of n1/n2. So even if they all come in at the same angle u_i as in the case of sunlight, they will come out at different angles and hence I will be able to see all the different colors. So that is why I am able to see different colors in a rainbow, because there is air and water involved. As an aside also note that the above paragraph tells us that the fact that a straw in a water glass looks bent and the colors of the rainbow come from the same underlying physical equation! Cool isn’t it? This is another aspect of scientific methodology, i.e., link together as many apparently disparate facts as possible as arising from one underlying phenomenon.

Wait a minute, this cannot be right. What I said above cannot be the whole truth. Why is that? It is because of fact 2 above. The sun is on the opposite side of the rainbow. So I cannot possibly be seeing bent light, I must be seeing reflected light that bounced off something. So, what did I miss? What I missed is hidden in that messy formula in the previous paragraph. Recall that sine function takes values from -1 to 1. So if n1/n2 is bigger than 1, that equation can never be satisfied for all values of the angle of incidence. What is wrong here? Clearly I can shine light at whatever angle I wish, so placing a restriction on u_imakes no sense. So, ask again, what did we do wrong? What we did wrong was to assume that there is always a refracted ray, i.e., a ray that goes into medium 2. What the “impossible to satisfy” equation above tells us is that beyond a particular angle all the light will be reflected back into medium 1 if n1/n2 is bigger than1. This phenomenon is called “total internal reflection”. If medium 1 is water and medium 2 is air in the earlier picture, then n1is bigger than n2 and light incident at large angles will be reflected back into the water. So, in the context of the rainbow what is happening is along the lines of the figure shown below. The light from the sun enters the raindrop, gets refracted at the front edge of the drop, travels through the drop, gets internally reflected at the back edge of the drop (i.e., the back edge of the drop is acting like a mirror) and then comes back out of the front edge again. And this is the light that you and I on earth see as the rainbow. So we have established that we need refraction and total internal reflection to account for the colors and the fact that the rainbow is on the opposite side to the sun with respect to the observer (jargon for you and me).

Still with me? Just hang on for a little bit more. We only have one fact remaining that we have yet to explain, the fact that the rainbow is indeed a bow. Again the answer lies in the discussion earlier. We just have to tease it out. Let us do this by first noting that the picture in the previous paragraph is clearly an oversimplification. What is really happening is more like this picture below. Light rays from the sun hit the drop and they are reflected and refracted at each interface. And you are standing in such a position that you get only one of a total of four outgoing rays from the drop. So the amount of light that is reaching you is a pretty small fraction of the light that fell on the drop. That is why we made such a big deal about the total internal reflection thing earlier, for it cuts out one of the outgoing rays and increases the intensity (brightness) of the one we get to see. Secondly the reflected light is diffuse. What does this mean? The sun is far enough away that all the light coming from the sun can be thought of as parallel rays. If the interface at hand was flat, then all the reflected/refracted rays will be in the same direction, yes? (Just generalize the picture in the first part of the discussion to many rays to see this). But our interface is a spherical water drop. So, even though the incoming light is all in the same direction, the outgoing light is going to be all over the place. And my eye is a pretty small hole in the scheme of things and I am only going to get a ray or so of the reflected light, not enough to see anything [2]. But I do see the rainbow. How?

This part is slightly more messy to state so bear with me. Let us revisit the picture in the paragraph on total internal reflection for a moment. Since the sun’s light is all parallel, the angle of incidence is going to change depending on where in the sphere the light hits. The angle at which the light comes out to the observer u_f depends on the angle of incidence as u_f =u_i -u_d where u_d is called the angle of deviation (just another name). Now, clearly, by repeated application of Snell’s law, I can express this angle of deviation as a function of the angle of incidence right? The details are unimportant for us. So let us just say u_d = f(u_i) for some known f. In order that I see as much light as possible, I need that u_f change as little as possible when u_i changes, yes? Which is of course the same as saying u_d or f must change as little as possible. Now, I remember from some calculus class I took ages ago that a function is “stationary”, i.e., changes as little as possible near the points at which it takes its minimum or maximum value. Do you remember this as well? So, I am most likely to see enough light to make out my rainbow when u_d is a minimum (you can easily convince yourself that you have to be on the moon or something to see the region when u_d is a maximum). For a drop of rain water and for red light this turns out to be a position such that your eye is located at an angle of 42 degrees to the direction of sunlight (look at the picture to see what I mean). Now, I clearly cannot change where the sun is or where the water is. So I just see all those water drops that make this angle with my eye. And viola! It is a bow!

Phew! We are done. We succeeded in explaining all the things we set out to explain. But just to throw a wrench in the works let me point out why you should not be happy yet. I can think of a 100 reasons but let me state the first couple that come to my mind. In all of the above, I thought of light as a straight line (ray optics). But I remember somebody telling me light is made of photons, little blobs of energy. I even remember learning that light is a wave just like the wave I can make in a string by oscillating it. WTF? How is it a straight line, a blob and a wave? On a totally different front (a front on which I don’t know the answer), I “know” that I see VIBGYOR when I see a rainbow. Hey! But white light is a “continuous” mixture of wavelengths (colors). So what this VIBGYOR business must be telling me is the degree of resolution in the cones of my retina? On the same note, what is it in the processing of images in my brain that leads me to see rainbows around light bulbs when I am drunk or sleepy but not otherwise? That is scientific curiosity for you and there is more than enough stimulus for it from the world around us to keep me occupied for the rest of my days![3]

[1] You can do the simplest of things, go to wikipedia and read this and this.

[2] It is over and beyond my patience levels to make a picture illustrating this. So I recommend that you go and play with this Java applet to see for yourself that this is true.

[3] Apologies on the length of this post. I “cross my heart and hope to die” when I say my future posts will be way shorter!

[4] After I uploaded everything in blogger I see that it has made all my theta's into u's. So the u in the text corresponds to theta in the images.

Scientific Communications in Web 2.0 Context

2007-07-03T15:09:00.000-07:00

This is a slightly out of context post that covers, instead of a particular aspect of science, some recent developments that may change the paradigms in scientific communications.

Despite the stereotype of lab-coat wearing geeks buried in their work with little connection to the outside world, communication is an extremely important aspect of a scientist’s job. Modern scientific research cannot be conducted in isolation. Hence scientists need to effectively disseminate information, whether presenting data in the informal settings of a lab meeting, or in more formal talks or posters at seminars and scientific conferences. Additionally, there is the matter of publishing scientific findings in technical journals and convincing peers about the importance their work while applying for grants. In a broader scope, scientists also need to spread knowledge to the general lay audience (especially in the current atmosphere of countries like the US, where scientists are being broadly discredited through active political agendas).

Traditionally, the World Wide Web has been employed by scientists as a tool to read/respond to e-mails, search and read journal articles (the old practice of going to the library to access paper copies of journals is all but obsolete), and search information on products, procedures etc (not to mention keeping bench scientists occupied while they wait for reactions to incubate or gels to complete their run). However, the role of the internet in science communication is rapidly expanding. Advent of the hyper-networked platform of the so-called Web 2.0 has particularly opened up excellent opportunities for scientists to both reach out to wider audiences as well as improve communication within their own community.

A major advance has been with respect to communication of science to wider audiences through mediums like blogs (this blog itself is a humble attempt in that direction). Previously, only a select group of science writers and a small number of publications could reach out to this audience. But given the ease of setting up and maintaining a blog and its potential reach, scientists now have an unprecedented access to audiences to talk about technical aspects as well as science policy, future etc. A good example is the wide assortment of blogs hosted under the banner of Scienceblogs, with a majority written by active science researchers.

On the technical side, two exciting portals that could possibly revolutionize scientific communications have come online in recent times. Late last year, the Public Library of Science (PLoS), a non-profit organization championing ‘open-access’ in science publishing, began a web-based journal called PLoS One. Other than being openly accessible to anyone with an internet connection (as opposed to ones that require paid subscriptions), this online-journal is distinguished by its criterion for acceptance: the peer-review process only considers the technical and methodological soundness of the scientific experiments, and accepts paper without any subjective considerations for perceived importance or relevance of the work.

While PLoS One accepts completed manuscripts, the highly reputed journal Nature recently launched a site called the Nature Precedings where scientists can submit pre-publication data and ideas in the form of ‘presentations, posters, white papers, technical papers, supplementary findings, and manuscripts’. Precedings does not have any peer-review system other than a check for completeness and scientific relevance (ie to make sure no non- or pseudo- scientific materials are being posted). Also, while PLoS One accepts manuscripts related to any ‘science or medicine’, Precedings is restricted to ‘biology, medicine (except clinical trials), chemistry and the earth sciences’.

Both Precedings and PLoS One submissions are assigned a unique number called the Digital Object Identifier (DOI) which enables other researchers to cite the articles in their own communications. Additionally, in both cases, the authors retain copyright of the articles through a Creative Commons License. Both sites also have Web 2.0 features such as RSS feeds and tags enabled.

But perhaps the most exciting feature on both Precedings and PLoS One is the ability of readers to comment on the published papers or posts, the idea being that science should be interactive and the connectivity of the web should enable researchers to participate actively in discussions with a broad audience. Additionally, the ability to vote on papers and submissions provides an alternative form of peer-review (a scientific equivalent of Digg?)

Therefore, unlike publishing in traditional journals, a process that takes a few months to complete, or presenting at a conference, only a few which are held and typically with a restricted audience, these portals will allow rapid dissemination of information to a large geographically unrestricted group of scholars. In some ways it is like presenting your data at a big conference, without the actual travel. Potentially, a huge beneficiary could be science in economically poorer countries (or even scientists with sparse budgets in developed countries), where researchers do not have the resource or funding necessary to attend many high quality conferences.

Another benefit of scientists widely using these services is the potential reduction of research redundancy. Especially in the interdisciplinary scenario of today, there are often two or more research groups employing similar methods for a single purpose. While competition is good in some cases, in this day and age of restricted budget for science, it is perhaps better to collaborate then compete.

However, the major concern for the success of such initiatives is whether enough scientific researchers will participate in submitting, commenting and engaging in a meaningful discussion. Old mindsets are difficult to change; currently, scientific scholarship is judged by the number of publications, but more so by the quality of the journals published in, as decided by their Impact Factor. Therefore many researchers would prefer to publish in traditional, arguably more prestigious journals. Moreover, in case of Precedings, it is possible that many laboratories around the world will be wary about releasing novel findings or new ideas for the fear of being scooped by others. Secondly, there is the concern about participation in the discussions. For example, while there are significant number of papers published in PLoS One, very few are commented on, leave aside carrying out an active discussion [1]. Nature’s previous attempt at an ‘open’ peer-reviews system was a failure of sorts as well. Some scientists may even view such activities as time-wasting diversions from real work. Another criticism, mainly for PLoS One, is the fact that the fees for publishing are rather high – 1250 US dollars, which might be too steep for scientists with low research budget.

Still, one can hope that with time, scientists will come to embrace the use of online resources for rapid sharing and discussion of their research. In the world of physics and mathematical research, the Cornell University maintained pre-publication portal, ArXiv, has achieved this goal with great success. It is time for all branches of science, especially the ever expanding biomedical sciences, to welcome the concept. Publishing or pre-publishing at sites like PLoS One or Preceding and obtaining high votes or encouraging active discussions should be looked upon as meaningful scholarly achievements. One can also hope for further engagement of internet technologies in science, e.g. laboratories using a Wiki-like platform to update their results, experimental protocols etc. Fittingly, I will cite this presentation posted on Precedings on how such a communication scheme will look like.

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[1]: PLoS has recently engaged the services of an Online Community Manager to encourage commenting. The job is held incidentally by a very active science blogger, who got the job in a very Web 2.0 manner, with the initial contact occurring through his blog !

Could life have started with Simplicity?

2007-06-28T21:24:00.000-07:00

One of the perplexing questions people ask in the origin of Life is how did such complexity ever evolve from a simple broth of chemicals in the prebiotic world. The first person to ever attempt to try to answer it was Harold Urey and Stanley Miller who created a chemical soup of ammonia (reduced Nitrogen), methane (reduced C), and hydrogen (should be present in a reduced atmosphere) and subjected the soup to electric discharge (simulating lightning and solar radiation). This experiment was performed in the 1950s and was done to simulate early Earth condition. After this electric discharge passed through the soup, simple amino acids and sugars and the raw materials for nucleic acid bases such as adenine were found to be created in this mixture [1]. These are all the raw ingredients for biochemistry to start hence bringing evolution of the origin of life into the realm of experimental science for the first time. Even though, the conditions of early Earth have come into question since then, Urey and Miller deservedly received a Nobel prize for the novel aspect of their work. In fact, the experiments were repeated recently with nitrogen gas instead of ammonia, carbon dioxide instead of methane, and hydrogen or water (currently accepted conditions for early Earth), and the products from the broth were similar in nature to those found in the Urey-Miller experiment.

In the prebiotic world envisioned by most scientists, chemistry would have dominated the changing scenario and landscape found in Earth. Chemistry, unlike biochemistry, is very non-specific and would create a huge pool of chemicals. Under the assumption that there were signs of modern cellular organisms in that pool (and this is a big assumption made out of necessity), then all or most of the biochemical reactions would be a small subset of all the reactions occurring in this pool called protometabolism [2]. Somehow, after the first catalyst were formed (not as efficient as modern enzymes), those catalysts were more specific towards a subset of these reactions and made these reactions occur at a faster rate leading to a feedback mechanism by which these reactions became the dominant reactions leading to the biochemicals or life as we know it now.

One such theory of the origin of life states that an autocatalytic reaction cycle was present in the chemical gemisch in the prebiotic world and by the nature of it being autocatalytic, it started dominating this prebiotic world leading to the first signs of life [3-6]. One such autocatalytic cycle is the tricarboxylic acid cycle (TCA or Krebs or Calvin cycle), which is present in all modern organisms in one form or the other [7]. The TCA cycle is the only route of carbon fixation into biochemicals starting with carbon dioxide as the source of carbon [8,9]. In one form of the cycle, called the reverse TCA cycle (and found in few organisms), the overall reaction can be visualized as 2 molecules of carbon dioxide (found in prebiotic earth) reacting with a molecule of citrate and 6 molecules of hydrogen to form 2 molecules of citrate and 5 molecules of water. The important thing to note is that 2 molecules of citrate were formed from 1 molecule of citrate hence producing more of the reactant. In other words, 2 molecules of citrate can be used as reactant in the next round of the TCA and the cycle is hence called autocatalytic. As it is autocatalytic, once prebiotic conditions existed where this cycle could take place completely (all reactions in it have to take place), this cycle would have taken place much faster after some time and would have slowly dominated the early prebiotic metabolism.

In addition, in modern cells, the TCA or the rTCA cycle is at the center of a cell's metabolism. In other words, the intermediates of the TCA cycle form amino acids, nucleotides, and cofactors for the rest of the cellular machinery. So, after this cycle starts to dominate the prebiotic world, the side reactions would start producing amino acids and nucleotides leading to complexity required for biochemistry to begin [8]. However, the conditions required for this cycle to take place completely have not been found so far. Secondly, the source of energy of these reactions and the compartmentalization of these reactions (to cause insignificantly higher concentration of these biochemicals) is still a matter of speculation and further research.

It was postulated that in early prebiotic conditions, these reactions could have taken place on clay or on metal sulfide surfaces such as FeS. These metals would have themselves been oxidized to ferric sulfide providing energy to take place to completion [3,4]. Another theory is that it may not have been just the TCA cycle but some other cycle like the ribose cycle that could have been at the origin of metabolism [5]. The advantage of the ribose cycle is that unlike the TCA cycle, there are only 1 or 2 reactions in the cycle that do not take place at an appreciable rate without a catalyst and hence only 1 or 2 reactions need the clay or metal surface as a catalyst.

In either case, it is a question whether an autocatalytic cycle should be considered as life. In my opinion it should not, even though it is producing more of itself (chemical form of reproduction) at the end of the day and there is energy conversion in the cycle (metabolism). It is just that life is very specific and driven unlike early chemistry which would have been highly aspecific. But this is certainly a matter of speculation and discussion.

[1] Biochemistry - Stryer.
[2] Singularities - de Duve.
[3] Wechterheuser - Evolution of the first metabolic cycles - PNAS, 87:200-204, 1990.
[4] Wechterheuser - On the chemistry and evolution of the pioneer organism - Chemistry and Biodiversity, 4:584-602, 2007.
[5] Orgel - Self-organizing biochemical cycles - PNAS, 97:12503-12507, 2000.
[6] Smith and Morowitz - Universality in intermediary metabolism - PNAS, 101:13168-13173, 2004.
[7] Wikipedia entry on Citric acid cycle.
[8] Morowitz, Kostelnik, Yang, and Cody - The origin of intermediary metabolism - PNAS, 97:7704-7708, 2000.
[9] Srinivasan and Morowitz - Ancient genes in contemporary persistent microbial pathogens - Biol. Bull., 210:1-9, 2006.

PS: Stanley Miller passed away this year at the age of 77 and this post is dedicated to him.

Resolving the panorama

2007-05-29T10:35:00.000-07:00

This post is about image stitching methods used to make a panoramic image. Panoramic images have become important in the digital age. Initially, panoramic images were developed to increase the field of view on the photograph. In the digital age, because one cannot print out pictures with resolutions less than 200 dots per inch (explained here), the method to take print outs for posters is to take a number of photographs with at least 15% overlap and stitch them together later using some software. In order to take the individual pictures that make a panoramic picture, the best technique involves using a tripod so that the camera lens only moves on a sphere eliminating parallax error. In addition, the aperture and shutter speed should not vary between the various pictures. More tips on the techniques of panoramic pictures can be found all over Google or by sending an email to me. This post is more about the science behind stitching the images of a panoramic picture.

The idea of image stitching is to take multiple images and to make a single image from them with an invisible seam and such that the mosaic pictures remains true to the individual images (in other words, does not change the lighting effects too much). This is different from just placing the images side by side because there will be differences in the lighting between the 2 images and that would lead to a prominent seam in the mosaic picture.

This Figure shows 3 photos and the locations of the seams are shown in black boxes on each picture and the final mosaic formed from all three pictures.

The first step is to find points that are equivalent in 2 overlapping pictures [1]. This can be done by taking into consideration a certain amount of pixels in the neighborhood of a pixel from 2 pictures and finding the regions that overlap in colors between the 2 pictures. Then the images are placed or warped on a surface such as a cylinder (because the panoramic picture is a 2-dimensional representation of the overlapping pictures in a cylinder quite often). After this step the curve is found that gives the most amount of overlap between the equivalent pixels on both images. Then the images are stitched together with color correction. I will deal in this post with the various algorithms for color correction.

This figure is an example of the Feathering approach.

1. Feathering (Alpha Blending): In this method, at the seams (the regions of overlap), the pixels of the blended image are given colors that are effectively linear combinations of the pixel colors of the 1st image and the 2nd image. The effect is to blur the differences of both images at the edges. In this method, an optimal window size is found so that the blurring is least visible.

This figure shows the optimal blend between the 2 figures in the previous figure.

2. Pyramid Blending: In addition to the pixel representation of images, images can also be stored as pyramids. This is a data compression method in which a the image is stored as a hierarchy or pyramid of low-pass filtered versions of the original image so that successive levels correspond to lower frequencies (dividing the images into different layers that vary over a smaller or larger region of space so that the sum of it gives you the original image). During the blending method described above, the lower frequencies (which vary over a larger distance) are blended over spatially larger distance and the higher frequencies are blended over a spatially lower distance [1] causing a more realistic blended image to be formed. Here during the pyramid forming process, the 2nd derivatives of the images (Laplacian) are taken into consideration while forming the pyramid and the blended pyramid is formed and reintegrated to form the final blended image.

This figure shows the pyramid representation of the pixels in an image and the pyramid blending approach.

3. Gradient Domain Blending: Instead of making a low resolution mapping of the image as above, the gradient domain blending method requires the calculation of the 1st derivative of the images. Hence, the image resolution is not reduced before the blending process, but the idea is the same as above. This method is also developed to find the optimal window size for alpha blending and is adaptive to regions that vary fast or slower.

This figure shows the gradient blend approach.

Sources:
[1]: http://www.cs.huji.ac.il/course/2005/impr/lectures2005/Tirgul10_BW.pdf
[2]:
http://rfv.insa-lyon.fr/~jolion/IP2000/report/node78.html

Wikipedia article on feathering.

All figures taken from http://www.cs.huji.ac.il/course/2005/impr/lectures2005/Tirgul10_BW.pdf

Biological Control - Doing it yourself.

2007-05-24T10:32:00.000-07:00

It was not too long back that the whole of biology was very protein and DNA centric. The reasoning was that proteins were used to do all the work in the cell - be it chemical work (enzymes), or physical work (motors, and pumps). DNA was important because it provided all the information to make the proteins and contain the set of genetic instructions that are passed on from generation to generation. For long, there was a battle whether DNA was more important or proteins were more important neglecting DNA's chemical cousin RNA.

RNA was considered as a step required in modern organisms to convert DNA to proteins. RNA is made up of nearly the same chemical constituents as DNA but it is more flexible and can have wide ranging 3 dimensional structures unlike DNA's double helical structure. However, this increased flexibility comes at a price - RNA is more unstable and in modern cells, a single molecule of RNA does not remain functional for long periods of time (mean life time is approx 5 minutes in E.coli).

Of course, all this changed when it was found that RNA molecules could be used as catalysts and even in modern day cells, there are some RNA catalysts also called ribozymes (and the list of ribozymes discovered keeps increasing). RNA captivated the imagination of biologists as this was a molecule that could store genetic information as well as be used as catalysts - taking on the dual role of enzymes and information storage. All of a sudden, RNA was considered to be at the origin of life as we know it. However in the RNA world hypothesis, one should take into consideration that it is not that only RNA is present. It only postulates that RNA is present and is dominant but other biochemicals such as peptides (small proteins) and DNA oligomers (small DNA molecules) are also present and aiding life (idea originally proposed in [1]).

One of the biggest controversies against the RNA world hypothesis has been that it does not play that big a role in modern cells. However, it has been found more recently that there are many RNA control elements in the cell. One such control element is the riboswitch. For a gene to be made, the DNA gets converted into a message called the mRNA (messenger RNA) which later gets converted to the protein equivalent to that message. It has increasingly been found that mRNA do not contain only the message to be read but certain control elements could also be present in the mRNA. These control elements are called riboswitch.

Lets take an example. Supposing you want to make Vitamin B1. There is an intermediate in its biochemical pathway called thiamine pyrophosphate (TPP). TPP is also important for nucleotide (the chemical constituent of RNA and DNA) and amino acid (the chemical constituent of proteins) biosynthesis and is important for the cell to have the right amount of TPP channeled into the different biochemical pathways. When too much of TPP is present in the cell, TPP binds to a certain riboswitch in it's own biochemical pathway. This causes the riboswitch [2] to suddenly have a defined 3-dimensional structure (from an earlier random or semi structured RNA element). This defined 3-dimensional structure also blocks the production of the protein for making more TPP. The switch in the mRNA turns the production of the protein that makes TPP on or off depending on whether enough TPP is present in the cell or not - hence regulating the production of TPP itself. So far, riboswitches are found more in the microbial world and are only now being found in the eukaryotic world.

Now, in the latest issue of Nature, the first riboswitch that controls splicing in higher organisms such as fungus has been found [3]. Splicing is the mechanism by which parts of the mRNA are removed before the protein is made so that parts of the DNA never translated in the protein. Alternative splicing is the mechanism by which a single gene at the DNA level can be translated into multiple protein molecules. This is done by excising different parts of the mRNA (excising the DNA only in one situation and not another) before it gets converted to protein. Splicing and alternative splicing occurs only in eukaryotes and has also been discussed here.

Anyways, the first riboswitch in the mRNA have been found to function for alternative splicing purposes. The TPP biochemical pathway discussed above is the system that they found riboswitches in. In this case, when TPP was present, the riboswitch forms a three dimensional structure that avoids splicing and the protein that is formed can not make more TPP. So the objective was again control of TPP concentration in the cell but the means used was alternative splicing instead of just blocking formation of protein. The implications of these results will only come out with time, but there is speculation that this opens up a whole pandora's box on riboswitches that could be found in eukaryotes.

[1] The Genetic Code - Carl Woese, 1968.
[2] Thiamine derivatives bind messenger RNAs directly to regulate bacterial gene expression. Wade Winkler Ali Nahvi & Ronald R. Breaker. Nature 419, 952 - 956 (2002).
[3] Control of alternative RNA splicing and gene expression by eukaryotic riboswitches. Ming T. Cheah, Andreas Wachter, Narasimhan Sudarsan & Ronald R. Breaker. Nature 447:497 (2007) and its companion discussion article - Molecular biology: RNA in control. Benjamin J. Blencowe & May Khanna. 447:391 (2007)

pdf of all cited aritcles avaiable on request

Battle of sexes

2007-05-21T12:26:00.001-07:00

Human Beings are diploid – that is each of us contains a copy of chromosome from our Mom and one from Dad. This gives us the advantage of having a spare copy of any given gene. However, there are certain genes that are "marked"in the embryo in such a way that either the Mom's or the Dad's copy is selectively silenced. The end result is that some genes in our body come with instructions attached, I am from Mom, Use only me! or vice- versa. The process that does this is called imprinting – either maternal ( for use only Mom’s gene) or paternal ( for use only Dad’s gene).

Why develop this curious phenomenon? On the surface it seems to be counter productive to us humans. If the marked/imprinted gene is defective then there is no working copy left since the silenced copy form the other parent can never be used. So why evolve such a complex yet dangerous mechanism? Since the process became known to scientists in the early 60s, several hypotheses have been put forth as to why this must occur. One of the most popular one shows the peculiar nature of inherent in a gene – its selfishness.

The Haig hypothesis is simple - it relates the development of a baby to the parent's inherent fidelity. The hypothesis, put forth by David Haig, predicts that Mom and Dad have different interests when in it comes to the development of their baby in any non-monogamous species, and hence imprint genes that are involved in growth of the embryo. Simply put both Mom and Dad fight a genetic war when it comes to the baby, more so if either one of them is prone to promiscuous!

Is there evidence for this prediction?
There is an excellent study done with the “deer mice” Peromyscus. This is a perfect species genus as we have both monogamous and polygamous species that can interbreed namely, P. maniculatus and P. polionotus. The females of the dark brown Peromyscus maniculatus species are promiscuous (babies within a single litter often have different fathers). Peromyscus polionotus, the sandy mouse, however pairs for life.

Check scenario one - Dad screws around but Mom is faithful.
In this case, the dad knows that the chances that all the offspring that she might carry are all his is slim. So he has to think of a way to make sure his baby grows faster at the cost off all other siblings and even mom.

This is exactly what you see when mate the faithful Peromyscus polionotus female with the
P. maniculatus male.The pups obtained are huge and mothers die giving birth.
Reason ? Well, the Peromyscus maniculatus dad has put a copy of a gene that ensures his baby grows faster since the female of his species is promiscuous. But the poor faithful Peromyscus polionotus mom is not used to playing this war and hence has no defense against the signals he is sending in. So the babies, prompted by Dad's genes grow unchecked, use up the mom’s resources and kill mom.

Check Scenario two - Mom is promiscuous but Dad is not.
The mom knows that since all the litter she carries has her genes, she can spread her genes in the population if she can restrict the growth of any one fetus, to conserve resources for her offspring with other males. So the genes she imprints will slow fetal growth.
That is what happens when you mate the promiscous P. maniculatus females with a steadfast Peromyscus polionotus male - you get tiny pups.
What happens? In this case, the mom is using her imprinted copy to slow down growth of the babies but the counterpart signal to grow is never received from the dad. The result is puny babies.

What if both parents are not promiscuous or vice versa?
The offsprings from a P. maniculatus cross or from a Peromyscus polionotus cross are healthy and similar in size. Reason? Each partner has co-evolved the defenses. In case of the promiscuous pair, the dad signals the babies to grow faster and mom to grow slower. In the other pair, each parent has the same vested interest in the offspring. End result is a normal sized litter.

What about humans?
So far about 80 of the 30,000 or so genes in the human genome are currently known to be imprinted. More importantly, most of these genes seem to play a role in directing fetal growth! And in the expected direction if humans were not considered to be monogamous-- genes expressed from the dad’s copy generally increase resource transfer to the child, whereas maternally expressed genes reduce it. So our genes behave much in the same way as the promiscuous mice! However there are imprinted loci are also implicated in behaviour/ neurological cases (Prader -Willi Syndrome) indicating that there is more to understand about this phenomenon.

More support for the theory comes from early indications that of very little imprinting in in fish, amphibians, reptiles and birds. Since the hypothesis states that imprinted genes are linked with acquiring resources from parents, this makes sense. But imprinting does also exist in seed plants where the endosperm tissue acts as the placenta to feed the embryo. Why this is the case is still unclear. There is lot of research that is ongoing and more that needs to be done. As molecular tools improve, we will be dissecting roles of imprinted genes much easily.

Ref:
1. Dawson, W.D. Fertility and size inheritance in a Peromyscus species cross. Evolution 19, 44−55.
2. Vrana Et. al., Genomic imprinting is disrupted in interspecific Peromyscus hybrids, Nature Genetics, 20, 362 - 365

Global Warming Facts - Part 1

2007-05-13T09:38:00.000-07:00

(I'm referring to news articles rather than scientific articles, and avoiding technical discussions in order to keep this article readable to everybody.)

If I told you that the Ganges and the Brahmaputra will both dry up by the year 2035, how hard would you laugh at me? Now, what if it was the world's leading scientific authority on climate change that told you?

I'm sure every one of us knows at least a little bit about global warming: that it is primarily caused by the greenhouse effect, and that greenhouse gas levels in the atmosphere have been rising because of industrialization and deforestation, that rising global temperatures will melt polar ice caps thus causing sea levels to rise, and so on. However, until recently, we've all been led to believe that we have a century or two to cut greenhouse emissions and quell the problem. The key phrase there is "until recently", because climate science has now progressed enough to tell us how bad the situation really is.

How bad will India be hit?
The first sentence of this article must have sent alarm bells ringing in your head. But a little thought will tell you why the Ganges will dry up, if not when: the Ganges, and indeed all perennial rivers in North India, are fed by glaciers in the Himalayas. As global temperatures rise, the glaciers receive snow later and start melting earlier, causing them to gradually fall back to the colder regions. This news article [1] in the Hindu has a detailed discussion about the effect of global warming on glaciers. The world's leading authority on climate change, the Intergovernmental Panel on Climate Change (IPCC), believes that all North Indian rivers will turn seasonal, and ultimately dry up by the year 2035 itself if global warming remains unchecked.

But there's more. Another news article [2] confirms our worst fears: inundation of low-lying areas along the coastline owing to rising sea levels; drastic increase in heat-related deaths; dropping water tables; decreased crop productivity are some of the horrors outlined for us. Falling crop productivity due to the change in the length of the seasons is of particular concern, because there is an acute shortage of arable land in our country. With the population still growing rapidly, and crop productivity dropping, combined with the fact that we are already facing a grain shortage this year and have been forced to procure from abroad, the situation appears dire.

Is it fair? The major contributors to the greenhouse effect thus far are the developed nations, and even on an absolute basis (let us not even go into a per-capita basis), India's contribution to global warming is very little. And yet, we will be among the first to suffer its effects, as the change in climate will decrease crop productivity near the equator but actually increase it in the temperate regions. Effectively, the third world has been offered a very raw deal: suffer for something you didn't do, and still bear the yoke of cutting emissions because, frankly, at this point our planet needs all the help it can get.

How high is safe?
Let us leave India's concerns aside for now, take a step back and look at the global picture. Global temperatures have risen about 0.6 C on an average in the past century. There is a worldwide consensus among scientific circles that the adverse effects of global warming will probably be manageable for a rise in temperature upto 2 C, but beyond that, melting ice caps, unbalanced ecosystems, drastically reduced crop yields, etc. will cause worldwide disaster of monstrous proportions. If I haven't painted the picture clearly enough for you, read this article [3] and this article [4] detailing exactly what countries like Canada and Australia can expect in terms of "disaster".

But, is this where you heave a sigh and think, if it takes a century for the temperature to rise 0.6 C, then we have plenty of time to remedy the situation before the rise reaches 2 C? Wrong. You see, there is a lag between the rise in greenhouse gases and the rise in global temperatures. Scientists give the analogy of heating a metal plate directly, and then indirectly, by placing a metal block between the plate and the heat source: when you place the block, it takes some time before an increase in temperature at the heat source affects the plate; at the same time, if the heat source stabilizes or drops in temperature, the plate will continue to increase in temperature for a while before stabilizing or dropping. Thus, the increase in temperature now is a direct effect of rising greenhouse gas levels sometime in the 20th century. We are yet to reap the effect of the carbon dioxide we are currently dumping into the atmosphere! And the fact is, the amount of greenhouse gases that have been going into the atmosphere has been steadily accelerating over the past century.

So, where should we hold greenhouse gas levels in order to hold the global temperature rise to 2 C? The answer cannot be explained in one sentence, because there is some statistics involved. We cannot accurately predict the temperature rise from carbon dioxide levels yet; we have to talk in terms of probabilities. A recent study by Meinshausen et al. [5] gives some startling numbers. This is actually explained in much simpler terms in this press article [6]. The gist of it is that, we are already past the safe limit! You see, the current level of greenhouse gases in the atmosphere stands at 459 ppm of carbon dioxide equivalent (the actual concentration of CO2, corrected to include the effect of other greenhouse gases). According to the Meinshausen study, if atmospheric greenhouse concentrations are maintained at 450 ppm, the probability of global temperature rise crossing 2 C reaches unacceptable levels (> 50%). The current EU target is 550 ppm - at that level, we will be looking at a rise of around 3 C! In other words, emissions across the world should already be decreasing, not increasing at an accelerating pace. Countries around the world should be spending a significant percentage of their GDPs to save the planet, but everyone seems reluctant to move.

Panels and Reports
I had mentioned the IPCC earlier. The IPCC was formed by the UN and has actually been around since 1988. Over the years, it has established itself as the world's leading authority on climate change. It publishes its findings periodically, the assessment reports published this year being the fourth set, and the most controversial one because it reads more like a disaster movie script than a scientific report. Actually, there had been protests over the previous report that the IPCC is being alarmist, and the UK government ordered an independent study be made (a committee was appointed, led by Nicholas Stern), and its findings were released at the end of October 2006. The Stern Review actually reported that the IPCC had understated the situation in the third assessment report. You see, climate science is far from exact, and the IPCC tends to err on the conservative side. There are already publications that say that the IPCC has been conservative even in the fourth report - read this news article [7].

Perhaps the most important thing that the fourth assessment report has accomplished is that it has finally laid to rest claims that global warming is a myth. Yes, until a few years ago, there wasn't even a global consensus on whether global warming is the fault of man, because the waters got muddied by studies that showed that greenhouse gases, while absorbing heat radiated by the earth, happened to reflect sunlight coming in, thus reducing temperatures. Further, it is believed that geologically, the world is headed towards an ice age. Increasing global temperatures were attributed to periodic properties of the Sun! Now, at last, all these speculations have been laid to rest, and IPCC has stated that there is a 90% probability that the phenomenon of increasing global temperatures is anthropogenic (caused by man), and primarily because of greenhouse gases - what we've suspected all along. India, too, has finally woken up to the threat, and has set up a panel [Citation needed] to investigate the specific effects of global warming on India over the next few decades, and what remedial measures are feasible. The panel is to be headed by Mr. Pachauri himself, the current head of the IPCC.

To be continued...
In the next part: The Kyoto Protocol, Emissions Trading, Extreme weather events, Bush-bashing, cows, bees and more!

References

[1] The Great Himalayan Meltdown
[2] Climate Change Will Devastate India
[3] Dire consequences if global warming exceeds 2 degrees says IUCN release
[4] Two degrees of separation from disaster
[5] M. Meinshausen "What Does a 2 C Target Mean for Greenhouse Gas Concentrations? A Brief Analysis Based on Multi-Gas Emission Pathways and Several Climate Sensitivity Uncertainty Estimates." in H. Schellnhuber, et al., eds. Avoiding Dangerous Climate Change (Cambridge University Press, New York, 2006)
[6] The rich world's policy on greenhouse gas now seems clear: millions will die
[7] Some scientists protest draft of warming report

Attention Concerned Scientists in IN, KY and OH

2007-05-09T07:42:00.000-07:00

If you are a scientist in Kentucky, Indiana or Ohio and are concerned about the scientifically inaccurate materials at the Ken Ham's Creationist museum, please sign this.

Statement of Concern
We, the undersigned scientists at universities and colleges in Kentucky,
Ohio, and Indiana, are concerned about scientifically inaccurate materials at the Answers in Genesis museum. Students who accept this material as scientifically valid are unlikely to succeed in science courses at the college level. These students will need remedial instruction in the nature of science, as well as in the specific areas of science misrepresented by Answers in Genesis.

Via Pharyngula

Is there anybody out there?

2007-05-08T09:46:00.000-07:00

This piece in November promised a lot more and I have failed to deliver on my promise so far. This is my first attempt to catch up with what I had promised. This post will deal with the chemicals that one finds in asteroids that land on Earth and with it questions the possibility that the raw materials for life on Earth could have started by the availability of these chemicals and also discuss the possibility of panspermia.

First, I will start with astronomical spectroscopy. This is the method by which chemists identify the compounds present in space. When light or any electromagnetic radiation is passed through a sample, the sample absorbs and emits certain wavelengths of light better than others and the wavelengths that are emitted and absorbed can be used as a fingerprint analysis of the chemical nature of the compound itself. Unfortunately, the science is not as simple* as I mention here but will suffice for the discussion that follows.

There have been many meteors that have hit the Earth's surface and some of these impacts have been seen as the reason for major climate change in the Earth. The interest in astronomical spectroscopy was purely to understand the physical and chemical nature of the universe around us. But as soon as astronomical spectroscopy developed into a reliable science, it stood to reason that it could lead us to understand how life on Earth originated and whether there are traces of life elsewhere in the universe. Afterall, if life evolved on Earth, the chemicals responsible for life should have been present on Earth before that (and possibly elsewhere) and hence the chemical nature of these meteors became important to biology as well, but all these studies have not been localized to the meteors alone.

The interstellar medium is divided into the dense and diffuse kind. The diffuse interstellar medium is cold and icy material that is not too dense and is made up of neutral and charged ions of compounds of C, H, and N, and also contain compounds such as naphthalene, which are aromatic compounds. In the dense interstellar compounds, the temperature is close to 10K to 200K (freezing point is 273K) important compounds such as hydrogen gas, carbon monooxide, water, carbon dioxide, methane, methanol, ammonia and hydrogen disulfide were found among others. That is, it has a source for H, C, N, O, and S. Later, in some clouds they have also found organic acids and higher alcohols such as ethanol (pure delight!).

The meteorites that have hit close to home were found to be quite rich in the lower and higher organic compounds of the classes mentioned above but were also found to have trace quantities of natural as well as unnatural amino acids (natural defined as biologically natural), purines, and pyrimidines (the base compound in DNA and RNA). In addition trace quantities of phosphonates and other P containing compounds were also found (also found in DNA and RNA). What was also interesting is that some of these amino acids was found to be chiral in nature (like in biological systems). In other words, there is a way in space to make optically active compounds and not synthsize all the isomers in equal quantities. It is actively debated whether these meteors were contaminated by biologically active components on their way to the ground even though there is evidence that says that it was not contaminated.

To summarize, the raw materials for life to start could be found in meteors and other components of space and indeed, these compounds under the right condition could lead to life anywhere. I will deal later with attempts by scientist these days to understand how life started from these raw materials.

I would like to end with panspermia and I think wikipedia has a good definition - Panspermia is the hypothesis that "seeds" of life exist already in the Universe, that life on Earth may have originated through these "seeds", and that they may deliver or have delivered life to other habitable bodies.

It is kind of a whacky theory and people either do not believe it or do not want to believe it because it is a theory like intelligent design - once you have said it, there is no way to prove it right or wrong. It is a theory which is unscientific in nature. But one of the leading scientists believing in the theory was none other than the Nobel Laurette - Francis Crick. Finding these organic chemicals in space has only led to more evidence for this hypothesis.

* Before one performs spectroscopy of a sample, one has to attempt to purify all the compounds present in the sample which is not an easy job because the chemical nature of the substance is an unknown at the beginning. A variety of chromatographic techniques are used for this. In addition, even after the spectroscopy of the individual samples are performed, it does take some time to realize the exact chemical nature of the substance being examined.

References:
Wikipedia as usual - on Origin of life and Astronomical Spectroscopy and Panspermia.

Extraterrestrial Organic Matter: A review - William M. Irvine - Origins of Life and Evolution of Biospheres - Volume 28, 1998, 365-383.**
** I can provide the pdf of this document on request.

Starting with the parts and ending with the whole

2007-05-07T10:49:00.000-07:00

The focus of today's blog post is going to be statistical mechanics. In statistical mechanics, one starts with the properties of the atoms/molecules/ions in a system and try to understand how the whole system will behave. So, one starts with the microscopic properties of the components of a system and tries to understand the macroscopic properties of the whole system. The macroscopic properties here implies properties such as volume or temperature or pressure that one measures in an experiment physically. I will provide an example to make one understand how difficult this task is:

Now lets consider a box or cylinder filled with gas molecules. As each individual gas molecule is small in volume, to fill up the whole container, one would require a very large amount of gas molecules, lets just say, something in the order of a mole (A mole contains 6.023 * 10^23 molecules of the gas. This might sound enormous but is actually a small number in terms of molecules. To place things in perspective, 1 mole of water is contained in only 18 grams of water, and a liter of water typically contains 55.556 moles of water). Let us assume for simplicity that these molecules obey Newton's laws of motion and do not undergo any quantum effects.

Even under these conditions, the molecules are all moving and the total energy of the system would be the sum of each molecule's individual kinetic energy and potential energy. In addition, there will be forces acting on each molecule due to the neighboring molecules as well as the ends of the container. So, by Newton's law of motion, each particle will have a unique acceleration induced on it and the position and velocity of each particle continuously changes within the box. It becomes a hopeless situation to even try to follow an individual particle's position and velocity as the position of the other particles affect the potential energy and force of the particle we are interested in.

Hence, what one does is try to come up with a probabilistic approach as to how the system's macroscopic properties are affected by it's microscopic properties. Most of the theory that is dealt with in statistical mechanics are valid only when there is a sufficiently large number of particles (as the derivations that will come up in the coming weeks will show) and will not hold true under other conditions. Using statistical mechanics, one can go beyond the simple Newton's laws of motion and try to derive/explain the laws of thermodynamics that one can measure experimentally.

Books to understand Statistical Mechanics:
Chandler, David (1987). Introduction to Modern Statistical Mechanics.
McQuarrie, Donald (2000). Statistical Mechanics.
R.K.Pathria (1996). Statistical Mechanics.

Book to understand Thermodynamics:
Above books and
Callen, Herbert B (2001). Thermodynamics and an Introduction to Thermostatistics.

Some of the above discussion was also inspired from the Wikipedia article on statistical mechanics.

New Hope For Infertility

2007-04-14T08:49:00.000-07:00

In July 2006, Prof Nayernia published a paper in Developmental Cell where he showed that he and colleagues had created sperm cells from mouse embryonic stem cells and used these to fertilise mice eggs, resulting in seven live births.

Now, he has published in Gamete Biology another breakthrough paper. A team of scientist lead by Professor Nayernia has isolated mesenchymal stem cells from the bone marrow of the male volunteers and coaxed into becoming germ cells (partially developed sperm cells called spermatagonial cells). The genetic markers showed that these mesenchymal cells had indeed developed into spermatagonial cells. While in most men, the spermatogonial cells develop into mature, functional sperm cells, this natural progression was never achieved in this experiment.

(Image courtesy: Mail On Sunday)

Earlier Prof Nayernia had shown that when spermatogonial cells were created similarly from mouse bone arrow and transplanted into mouse testes, they underwent early meiosis but did not develop any further.

Talking about his newly published research paper, Prof Nayernia, of Newcastle University, said : "We're very excited about this discovery, particularly as our earlier work in mice suggests that we could develop this work even further. Our next goal is to see if we can get the spermatagonial stem cells to progress to mature sperm in the laboratory and this should take around three to five years of experiments.”

The experiments open a whole new avenue for not only infertile males, but also for gay couples. What was done with the male blood cells, could be done with female bone marrow. Exciting times, lie ahead.

A word of caution before the media rings this in as male infertility solved.
Firstly, the cells in this case have not developed into mature sperm.

Secondly, the earlier experiments with the stem cell redirected sperms had resulted in mice that had severe problems - they were all infertile and had breathing or walking difficulties. They also were growth impaired, either abnormally large or or small. And all had reduced life expectancy - they died within three days to five months of being born (normal lifespan is two years for healthy mice). Prof Nayernia had acknowledged then the abnormalities were probably due to genetic defects that arose in the creation of the sperm.

Of course, the technique has already provoked an ethical storm (and it was just published on the 11th!) and could soon be banned by the Government over concerns about the safety of using artificial sperm. Critics say that the treatment breaches moral boundaries, mostly because it would effectively render males redundant!! The technique could be adapted to grow eggs in a lab (and thus helping infertile women), but this seems to the critics a way of children being born through entirely artificial means!

Precaution needs to be taken before the use of this technique - the scientist themselves claim that work needs to be done, the process is far from perfect. But to blanket ban it would hurt several hundreds of infertile men (natural or those who underwent chemotherapy)..

Heights! Mapping the "Toy" Gene

2007-04-06T11:14:00.000-07:00

Domesticated dogs are amazing in their variety - pocket size Yorkshire terriers to Great Danes! Ever wonder what accounts for that disparity?

Wonder no more. This week's issue of Science sees a study published that gives us a clue to how a mutation in a single locus regulates size in these creatures.

A team of more than 20 scientists from eight institutions (United States and the U.K.) toured the dog show circuit and collected blood from 3,241 canines of all sizes and shapes. They found that the reduced growth mapped to a locus, near the IGF1 gene. In human IGF1 plays a role in the growth from birth till adolescence.

In all the "toy" dogs tested (distantly related and reproductively isolated), there were mutations in the region next to IGF1. This is intriguing to see a single change map to all the small breeds, indicating that the change probably maps to the time when dogs evolved from their wolf-like ancestors. The same "small dog marker" however, is not found in the modern wolves.

Why is this so fascinating? Mostly because the entire study pinpoints a single allele to be responsible for the phenotypic variation (small size) and the result was achieved without doing a single cross!!

Longevity- What needs improvement?

2007-03-29T12:09:00.000-07:00

S. Jay Olshansky, Robert N. Butler, and Bruce A. Carnes ask a simple question, What if Humans were designed to last? in the latest issue of The Scientist.

A coordinated network of molecular processes providing cells with nearly flawless surveillance, maintenance, and repair capabilities exemplifies the "perfection" of the human body. Living things need this precision in order to survive to reproductive
maturity in the face of a hostile environment and the toxic debris that the
cellular machinery of life generates. Meanwhile, subtle changes and imperfections at every level of biological organization give rise to the diseases and disorders associated with aging and impose limits on the duration of life, but ultimately, these changes and imperfections drive the evolutionary process itself. The juxtaposition of Michelangelo's perfection and Darwin's flaws embodies the linked stories of reproduction and death..

I particularly like that the authors say,

Our goal is not to create new methods of combating disease, but rather, to
spark an idea, trigger a thought, and inspire others to think outside the box by
first imagining a new future of human health that is better than the present -
and then working to make it so.

What do you think? If you could embark on making a long lived perfect human what would you change and why?

Discuss!

A Species Concept...How hard could it be??

2007-01-26T13:32:00.000-08:00

People have thought about the origins of closely related species for decades. In fact, scientific research on speciation can be traced all the way back into the early 19th century. By looking at older literature, we can understand old arguments, as well as, provide us with ideas toward current problems.

The evolution of biology is a like a history of unanswered problems that have been worked on by some of the most original thinkers of our time. This is very different from a field like molecular biology, where much of the older literature may be irrelevant due to advancement of the field. One of the first things that you should know is that researchers cannot come up with one universal definition of a species.

Speciation is a process that can be looked at from many points of view, whether it be by Behaviorists, Phylogeneticists, Systematists or Evolutionary biologists. So, when trying to decide on a single definition, many conflicting ideas come into play depending on the angle you are examining it from. Most often, the definition for a species, depends on the specific criteria you have set for boundaries.

As you can see, this is not as easy to define as it initially seemed. So, how do we begin to understand speciation?

First and foremost, it is best to understand the current definitions that are accepted for a species.

Then, tackle the problem of understanding the difference between concepts to finally be able to choose a definition that works best for you.

Species Concepts for Speciation:

1. Biological Species Concept (Isolation Concept) (BSC)

"Groups of actually or potentially interbreeding natural populations which are reproductively isolated from other such groups" (Mayr 1963)

"Systems of populations, the gene exchange between these systems is limited or prevented in nature by a reproduction isolating mechanism or by a combination of such mechanisms" (Dobzhansky 1970)

2. Recognition Species Concept
"The most inclusive population of individual biparental organisms which share a common fertilization system [specific mate recognition system]" (Paterson 1985)

3. Cohesion Species Concept
"The most inclusive population of individuals having the potential for phenotypic cohesion through intrinsic cohesion mechanisms [genetic and/or demographic exchangeability]" (Templeteton 1989)

4. Phylogenetic Species Concept (Character-based)
"An irreducible (basal) cluster of organisms, diagnosable distinct from other such clusters, and within which there is a parental pattern of ancestry and descent" (Cracaraft 1989)

5. Genealogical Species Concept
"exclusive' groups of organisms, where and exclusive group is one whose members are all more closely related to each other than to any organisms outside the group..." (Baum and Shaw 1995)

6. Evolutionary Species Concept
"A single lineage of ancestor-descendant populations which maintains its identity from other such lineages and which has its own evolutionary tendencies and historical fate" (Wiley 1978)

7. Genotypic Species Cluster Definition
"Distinguishable groups of individuals that have few or no intermediates when in contact..."

"...clusters are recognized by a deficit of intermediates, both at a single loci (heterozygote deficits) and at multiple loci (strong correlations or disequilibria between loci that are divergent between clusters)" (Mallet 1995)

From this list, 1-3 are process based, while 4-7 are pattern based. Many researchers are adamant that pattern not process should form the basis of any species definition while the others are just as adamant for the opposite.

A generally defined and consistently applied definition of species is vital for the study of diversity, as well as, phylogenetic investigations of diversification...which ultimately gives valuable insights into the study of speciation.

However, what previously seemed easy to define, is in fact a hot issue being debated to this day... with the science community still not using a single, general concept of what exactly defines a species.

I hope this opens up conversations as to what is a species, as well as, leads to interesting topics of speciation. I have given a foundation....so off you go now...

Do We Or Don't We?

2007-01-25T07:37:00.000-08:00

Carl Zimmer brings up a very important point that conservation biologists (and all the rest of us who care about this Earth) are facing right now. As climate changes occurs, species move away in search of their natural habitats (as previous records show). However, we now know there are several species that might die if we don't find them a habitat.
The pros for human assisted moves are obvious - we save a threatened species. The cons are numerous - such moves in the past have rarely succeeded, when they did it resulted in threatening the natural habitat where the species was moved or it end up producing "hybrid zones" to name just a few.
As Zimmer puts it, "Which is worse: the risk of creating a new invasive species through assisted migration, or just watching a species become extinct? "
We have a moral dilemma in front of us - I wonder what step to take?

What We Cannot See Threatens More

2007-01-07T20:30:00.000-08:00

So many people talk about terrorism with an idea of people in mind. We seem to concentrate on nuclear threats and how it will bring the demise of our human race. Since I am not able to foresee the future, I cannot eliminate this possible threat in the future...but in my view...I do not believe this to be the most imminent threat to our race. That is not what scares me....

With each piece of knowledge that I acquire, I am scared of the terrorists that I cannot see. The silent killers. The millions of microbes that have the potential to do more harm, in more places, at the same time, than any nuclear bomb. We live in a time when travel and international business is the way of the world. We move around so often and so quickly, businessmen often forget where they have been on a given trip. I applaud progress and fair business, but I also am afraid of what else travels along on these trips with any given person from place to place. People come into contact with organisms in new environments in which they have never been exposed and then in turn infect 10's if not 100's of people in a single afternoon.

Imagine the number of people you are near at the O'Hare airport in Chicago or Grand Central Station in NYC. Try to quantify the trail of contact of each person you are near...and ultimately where they go. The numbers are astounding and you feel as if you can't possibly tackle something this big. So, why do I call these microbes terrorists? That is simple. These microbes or whatever the latest attack is, is invisible to the naked eye, it evolves faster than we can sequence it, symptoms may seem like the common cold and does not have the ability to rationalize. We cannot sit in a room with these invaders, sign a treaty no one has any intention of keeping and walk away feeling like we have control. We are at the mercy of these invaders.

You may be wondering why this is a problem now more than ever in the past. Research and reports have been published explaining why we are at a greater risk now of new pathogens emerging. First and foremost, we are dealing with microbes that have "tremendous evolutionary potential". We are also faced with so many other things such as "changing climate, altered ecosystems, increased human contact with animals, new medical technologies that have created novel pathways for the spread of infections, and 'the rapid and virtually unrestricted transport of humans, animals, foods and other goods, which can lead to the broad dissemination of pathogens and their vectors throughout the world'". We are sharing and trading microbes into new environments not previous occupied. This is and will be an action that carries harsh consequences.

"Any of these factors alone can trigger problems, but their convergence creates especially high-risk environments where infectious diseases may readily emerge, or re-emerge...It is conceivable, in fact, that in certain places microbial 'perfect storms' could occur, and unlike meteorological 'perfect storms,' the events would not be on the order of once in a century, but frequent." We have in recent years experienced such occurrences that could have been much worse than they were, (i.e., SARS, avian bird flu, west nile). As we learn more with each passing day and from past epidemics, we must work together not as a country or countries, but as a race, to face such obstacles.

In the example of SARS, the result could have been devastating. One country, China, hid the outbreak for many weeks if not closer to months. Politics and tourism blinded what was truly important...its' people. Once the knowledge of a new epidemic hit the WHO, global cooperation began the process to stop the impending devastation. It is only due to laboratories around the world, working tirelessly for a common cause, that we are not writing about entire countries being wiped out. By May 17, 2003, the WHO reported 7,761 cases of SARS around the world with a death toll of 623. This was spread across 28 countries on 5 continents. Of those, 66 cases were in the US (no deaths), 5209 cases in mainland China with 282 deaths and 1710 cases in Hong Kong with 243 deaths. Although the number of cases seem high, the low number of deaths is due to a few dedicated and active people that rallied early to stop this from spreading even more. They were successful in their efforts of containing the cases early. However, an expert in human diseases caused by parasitic worms and a tireless foe of infectious diseases, a doctor once part of the doctors without borders and one of the doctors that preached, "stay close to the victims", did just that.

Carlo Urbani stayed close to the first victims of SARS. He monitored them himself and rid the area of unnecessary people that could be at risk. Urbani also was the first to act and begin to gather the people necessary to alert the world. Unfortunately, it was only a matter of time before he too fell victim to this outbreak. Urbani died with his wife and 3 sons following behind his casket. The SARS virus was so infectious that even another week's delay in recognizing the problem would have spread the germ to hundreds if not thousands more people before control measures were put into place, one nation at a time. This is what Urbani did for all of us. His quick action had limited the number of cases and his doctors said he had probably inhaled so much virus as he tried to treat so many people that he was doomed from the start.

I write this as an introduction to the continuing story of what really threatens us. We do not have any idea of what or where the next big terrorist will come from, or even the ability of science knowledge to combat it. I do not fear other nations and the weapons they hold as much as I fear microbes that can appear and evolve faster that we can identify common links. Researchers wait with dread of that never previously seen microbe that has the ability to jump across the animal-human line. This threat, in addition to combining with common viruses that we cannot control now, is what scares me!

References:
http://www.cdc.gov/ncidod/sars/factsheet.htm
http://content.nejm.org/cgi/content/full/348/20/1951
http://www.who.int/en/
M. Enserink, "A second suspect in global mystery outbreak". Science 299 (March 28, 2003)
M. Hamburg, J. Lederberg, B. Beatty, et al. "Microbial threats to health: Emergence, detection, and response" Institute of Medicine National Academy of Sciences. Namtional Academies Press, March 2003.

Ashley Treatment - Right or Wrong?

2007-01-06T07:50:00.000-08:00

Ashley Treatment is making waves in medicine. A young girl with static encephalopathy (severe brain damage) has undergone an operation to stunt her growth and keep her at a manageable size. This has created a big hue and cry over the net all over the world with some parents even linking it to eugenics.
When I first heard about the case I got squeezy too. I have been a fringe dweller in the world of autistic and mentally retarded people. My parents are actively involved in this cause back home and I have seen how difficult it is to take care of a 6 feet 2 adult with a mental capacity of a 2 year old. As difficult the situation is, parents rarely have thought of taking such extreme steps. So I wondered, Is this right? There are no medical precedents to this case. This may very well open up a slippery slope as pointed out by University of Pennsylvania ethicist Art Caplan. But let us look closely at the "pillow baby Ashley" case before we raise our voices to say this is wrong -
Shortly after birth, baby Ashley had problems feeding and lagged in development. Doctors diagnosed static encephalopathy (and still do not know the cause). The brain damage has left her in an infant stage - she is for all purposes a 3 month old - unable to hold her head, sit, roll or walk or talk and yet she is four feet five inches tall. That being said the girl is alert and goes to school for disabled children. However since her parents have not found a suitable care taker, they tend to the child at home themselves. There is no cure for Ashley (now and in the near future). She is going to be in the same state yet continue to grow bigger.
So her parents decided to stunt her growth to keep her smaller. She had her uterus and breast tissue removed and she received large doses of hormones to halt her growth. This will keep her small, reduce risks of bed sores and prevent her going through puberty (reducing the pain of periods and breast cancer which runs in the family). Her parents are taking care of her. Keeping her from growing is not going to make a difference to her - she is 3 month old mentally!!
Medical advances have meant that we can "save" lives that previously would not have a chance. At the same time, we really do not have the capacity to take care of severely handicapped people. Nor do we have a better support system for families that take care of the individual on a daily basis - 24/7. Some ethicist that say what Ashley's parents are doing is making the situation easy on themselves - yes, they are .. but try taking care of a infant that weighs like an adult for a whole day! You might change your mind too. On the other hand, the question to be asked is - who decides that this is the right thing for the parents to do? Take this scenario - What if a slightly challenged girl's parents decide that to save her from abuse in the future, we are going to prevent her from undergoing puberty. This girl is always going to be a minor legally. So do her parents have legal rights? Or should society intervene?
But society is not making the place safer in which case the parents would never have to make such decision. Realistically speaking, man kind is not going to make this earth into an Utopian paradise . Does this mean that this decision or others like it would be ethical?

Book Review

2007-01-03T06:58:00.000-08:00

Another good book by Carroll. Making of the fittest explains evolution using the evidence found in the DNA of every creature. Using DNA as evidence, Carroll weaves stories that tie creatures together and spin across millions of years and clearly explains how identical traits have evolved independently(and sometimes repeatedly) by natural selection.

The examples themselves are fascinating - evolution of anti-freeze protein in Artic and Antarctic fishes, color vision through duplication of Opsin genes in birds and primates, sickle cell anemia and resistance to malaria, eye development (an creationist favorite) to skin color in humans. In each case, Carroll explains the genetic changes that the DNA has undergone over the course of time to result in the developmental changes we see.

He has also explained how inaccurate is the creationist insistence that probability of mutations resulting in evolution is next to impossible. He uses very elementary mathematics to explain how advantageous mutations can spread through a population.

Carroll has also tackled head on the problem the US schools are facing now -the disingenuous ID believers who want to teach "creationist science" (which is an oxymoron). Using the Lysenko fiasco as an example, he has clearly illustrated what can happen if there is a deliberate ignorance of evidence.

Unlike Zimmer, reading Carroll does require some basic understanding of biology (high school level at least) but he is an adept writer and worth reading. It is a book aimed at curious people who would like to know more about Evolution and the evidence we have for it. I don't think Creationists or the IDiots are going to change their minds but I hope books like this one convince the fringe dwellers that Evolution is more than a "just" a theory. There are numerous examples of evidences - from geology to now molecular biology- to show how evolution has occurred. As Lewis Black said "We have Fossils. We win."

An Example Of Altruism?

2006-12-23T14:37:00.000-08:00

Many people have wrote that there is no such thing as altruism. I must admit that I have also always thought the same thing..even though I continued to search for one such act. I have often been the lone arguer pointing out that no one has been able to uncover a single example of true altruism...in a natural setting or in the human race. I am now rescinding my previous statement. I have for a very long time..searched for an example that I could in some way attribute to altruism..and until now I have been unsuccessful. I suppose all examples are based upon your own definition of altruism. I learned many years ago that altruism is an act done by an individual at a cost..benefiting another individual not of relation to the one performing the act.

The said example concerns a chimpanzee and a human. A researcher was following a group of chimpanzees in the jungle. After some hours, he found that he had forgotten his lunch back at the research station. This researcher then proceeded to try to knock down fruit from a tree some distance from where the group of chimpanzees sat eating their mid-day meal. It has been noted that after some time of unsuccessful attempts to acquire fruit... a young male from the group collected some fruits from a tree and climbed down toward the researcher. The chimpanzee then proceeded to approach the researcher and leave the fruit for the researcher.

This instance has been noted as a true act of altruism by any definition since the chimpanzee was not of relation to the researcher (not in the last 1000 years at least) and this act was a cost to itself with no benefit. Therefore, I stand corrected on the notion of altruism...it seems to exist after all.

References
Compassion, Rescue and the Altruism Debate, The emotional lives of animals Jeffrey Moussaieff Masson and Susan McCarthy.

Why We Should Always Question..

2006-12-19T14:09:00.000-08:00

There are many moments in time that we look back at now...which will always lead to us to slap our foreheads and say, "stupid, stupid, stupid". There is one such moment that continues to be brought up in the most general science classes..as if to say.."if you don't test and retest...we will ridicule you for years to come". This example is of course the lemming. Lemmings were believed to commit, "The Lemming Suicide Plunge" when the population became too numerous. It was really believed that millions of lemmings would be overcome by a hard-wired impulse to dash to their death by hurling themselves over a cliff to the rocks below or by plunging into the sea to die a horrible death by drowning. The reasoning behind this was thought to be a deep-rooted act of altruistic behavior resulting the greater good for the species. However, you can probably guess, this is not the case. Shown to the right is a famous Far Side cartoon dipicting natural selection in action. As the lemmings dash to their death..there is one cheater in the group that will survive and ultimately passing on the cheater genes to future generations.

How this story may have gotten started....

Many rodent species experience very strange cyclic population explosions. It is very interesting that lemmings have one of the most regular cyclic fluctuations in population densities. It has been shown that these little creatures have population explosions about every three or four years. The population numbers of lemmings explode to high numbers, and then drop almost to extinction. Even after approximately 75 years of intense research, scientists do not fully understand why the populations fluctuate so much. Throughout the years, many factors have been tested (i.e., changes in food availability, climate, density of predators, stress of overcrowding, infectious diseases, snow conditions, sunspots, etc) but none completely explain why populations of lemmings have these explosive cycles.

The myth of the lemming most likely started when these population explosions happen and the lemmings migrate away from areas with a dense population. As you can imagine, the migrations begin slowly and erratically. It has been shown that small numbers of lemmings will move at night, and larger groups in the daytime. This movement causes small groupings of lemmings to move instead of one continous mass, usually seperated by a short time frame of 10 minutes or so. It has been noted that they will often follow well worn paths and roads along their journey.

As you can imagine, there will be unavoidable obstacles, such as streams and lakes inevitalby causing them to swim as a last resort. Suprisingly, they are able to swim across a 200 meter body of water on a calm night, but most will drown in a windy night.

So why the myth began....

It is due to a very unlikely source....Walt Disney. Walt Disney was making a movie tittled, "Wild Wilderness" which was released in 1958. It was filmed in Alberta, Canada, in a location that is far from the sea and not a native home to lemmings. The lemming were imported and forced to jump to thier deaths by placing them on a spinning turntable that was covered with snow, and then shooting it from many different angles. The cliff-death-plunge sequence was done by herding the lemmings over a small cliff into a river. It's easy to understand why the filmmakers did this - wild animals are notoriously uncooperative, and a migration-of-doom followed by a cliff-of-death sequence is far more dramatic to show than the lemmings' self-implemented population-density management plan.

The moral of the story....lemmings do not commit mass suicide and Walt Disney has clear prejudice against the lemming and for the mouse.

Net Picks

2006-12-13T18:42:00.000-08:00

Something to read while taking a break -

Fifty Years With Double Stranded RNA
Alexander Rich, the scientist who discovered hybridization and the "other" double helix describes what it meant to biology.

Bioengineering and AIDS
University of Utah scientists designed a "molecular condom" women could use daily to prevent AIDS by vaginally inserting a liquid that would turn into a gel-like coating and then, when exposed to semen, return to liquid form and release an antiviral drug.

Genetic Map Offers New Tool For Malaria Research
In one of three genomic studies of malaria appearing in Nature Genetics, scientists chart genetic variation across the genome of the malaria parasite, unlocking novel DNA regions associated with drug resistance.

Laugh And The Whole World Laughs With You: Why The Brain Just Can't Help Itself
Researchers at UCL (University College London) and Imperial College London have shown that positive sounds trigger a response in the listener's brain in an area that is activated by smile, as though preparing our facial muscles to laugh.

This Holiday Season drink without fear.
A study performed by the Research Laboratories of the Catholic University of Campobasso (Italy) confirms the beneficial effects that moderate consumption of alcohol has on our health: drinking in moderation reduces all-cause mortality.

Another reason why the Octopus Rules - in built 3-D light reflectors!
Roger Hanlon at the Marine Biological Laboratory, Woods Hole, Massachusetts and colleagues took a close look at the octopus's skin and identified a new group of proteins (leucophores) with remarkable properties.

New Insights Into The Origin Of Life On Earth
In an advance toward understanding the origin of life on Earth, scientists have shown that parts of the Krebs cycle can run in reverse, producing biomolecules that could jump-start life with only sunlight and a mineral present in the primordial oceans.

Science Daily Picks

2006-12-06T14:18:00.000-08:00

Found : Apple Gene for Red
CSIRO scientist have found the gene that controls the color of apples. The red color of apple skin is result of anthocyanins (responsible for blue or red color in plants). It was known that color of apples is affected by light (less light results in poor color), so the scientist looked for genes that were activated by light and compared these to genes in a green apple and bingo!

Learning During Sleep?
Max Planck Institute for Medical Research in Heidelberg have taken a step towards understanding communication between memory areas. Their study shows a link between sleep and memory consolidation (transfer of memory from hippocampus to the cerebral cortex).

Cities Change The Songs Of Birds Leiden University researchers studied the songs of the great tit (Parus major), a successful urban dweller in the center of ten major European cities and compared the songs to that of the bird living in nearby forest sites. The results show that songs that are important for mate selection or territory defense are shorter, sung faster and at a higher pitch by the urban bird. The findings published on Dec.5 in Current Biology show divergence within a species because of the environment and could very well lead to speciation.

NASA Telescope Sees Black Hole Munch On A Star.
NASA’s Galaxy Evolution Explorer has caught a black hole eating a star, from the initial capture to the last bites.

Water Still Flows In Brief Spurts On Mars, NASA Images Suggest
NASA photographs have revealed bright new deposits seen in two gullies on Mars that suggest water carried sediment through them sometime during the past seven years.
So let the hunt for the ETs begin :)

Fruitless Attempts To Explain Behaviour Hardwiring

2006-11-20T11:18:00.000-08:00

About an year ago, Dickson lab had published an article about a behavioral switch gene, called Fruitless. It had gained notoriety in the popular press as the “Gay Gene” since it affects sexual orientation but to me Fruitless is interesting not only because it determines sexual orientation but more importantly as it gives a glimpse into how genes modulate behavior.
You see, behavior is “hard wired”into our nervous system during development. The neuronal body plan is already present in our genome - the developmental genes that direct cells to grow into a specific type or in a specific direction. These genes during development take cues from the environment and hard wire innate behavior in to a species. I have always thought that to be the coolest thing. Think about it - we are not only a function of our genes but also product of our environment. And Dickson's research links the two together - how a presence of a single gene product directs the function of neurons responsible for sexual orientation in fruit fly males. Courtship behaviour in D. melanogaster is invovles a series of well chorographed steps that invovle the visual, the olfactory, the tactile, the acoustic, the gustatory and the mechanosensory stimuli being exchanged between the sexes (See Fig.1). The role of the female is more simplified -she simply runs away, gives the odd kick, then mates (or not).

Fig. 1 Courtship behaviour in Fruitfly
This normal courtship behaviour seems to be disrupted in the Fruitess mutants. Before we talk about what happens when we mutate this gene, lets us take a brief overview of what is known about the gene. Fruitless gene was molecularly cloned in 1996 and the putative protein encodes a transcription factor. Fruitless is sex specifically spliced - in lay man terms it means that males produce one version of this protein where as the females produce another. This sex specific splicing is regulated by presence or absence of another protein called Transformer, which in Drosophila also determines the sex in the fly.
So what happens if you produce the wrong version of the protein in either sexes? By forcing males to express the female-specific Fruitless transcript by using the awesome power of Fly genetics (:P), the Dickson Lab produced males that were sterile, uninterested in courting females, actively courting males, actually ending up forming courtship chains (see this). By contrast, females making the male version of the protein mated poorly, produced very few eggs, but — astonishingly — courted other females (see this), even to the point of forming chains.
So why does this happen? When you look at the the central nervous system of males and females ,there are very few differences in terms of sex-specific Fruitless expression- in number, position or wiring of cells that express this protein. But Fruitless is present in the olfactory sensory neurons which play an important role in fly courtship behavior. So when male fruit flies cannot produce this male specific form or produce a mutant form of this protein, you get males that court other males. In other words, a single gene encoded product is enought to shift the functioning of the nervous system from male to female mode, irrespective of the morphological sex of the animal. Simply put with mutant (rather non-sex specific)versions of the protein, flies change their sexual orientation but they not other aspects of their morphology.

Now the same gene is making a news splash again – the Kravitz lab has linked Fruitless to yet another sex-specific behavior – aggression/ fighting patterns. Aggression found in almost all animals - from sea anemones to human - helps to acquire food/shelter/ mates or defend the same. Despite its importance, relatively little is known of the neural and humoral mechanisms that are its proximate causes. Many behavioral patterns in aggressive behavior are shared in flies but there are a subset that are sex specific. Female fighting, for example, largely involves head butts and some shoving. Males show extended wing threats, wing-flicking while retreating, and high intensity components of fighting like boxing, tussling and holding. In contrast to male fighting behavior, no clear hierarchical relationship results from the interactions between female flies.

Figure 2. Aggresion Behavior in flies

When the versions of Fruitless are swapped, the males fight like females (the sissies) and females lunge at their opponents as seen in the Figure 2 above. The top panel shows the normal aggresion patterns seen in males and females while the bottom panel shows what happens when the flies produce the wrong version of the protein. Panels e and f show males exhibiting female aggression pattern when they express the female version of the protein. When the sexes with the opppsite version of the protein are put together in the panel g and h. In panel g, the upright lunging fly is a female and so is the upright "boxing" fly in panel h , indicating that swapping the protien alters how the flies respond - another innate behaviour affected!

The question that still remains (the most important one) is what is the effector? What does Fruitless, a transcription factor, modulate in a gender specific manner to control the sex specific aspect of behaviour?

There is a lot to still uncover but we are finally beginning to glimpse at how a genes influence how we respond. I believe that most behaviour is hard wired but at the same time modulation of the behaviour is environmental dependant. And now we finally are beginning to tell the effect of nature on nurture. A fun time lies ahead in molecular neuroscience!

Reference

1 - Demir, E. & Dickson, B. J. Cell 125, 785−794 (2005).

2- Vrontou E, Nilsen, S. P., Demir, E., Kravitz, E. A. & Dickson, B. J. Nature Neuroscience - 9, 1469 - 1471 (2006)

Exploiting the parasites to our advantage

2006-11-19T18:15:00.000-08:00

In a recent paper (Oct 20, 2006) in the journal Science, scientists have reported the use of a parasite-specific machinery in to correct certain deficiencies in human cells, which can be then used to tackle critical genetic disorders in humans.

This is cool for several reasons: taking lessons from a one-celled parasite to apply and solve complex genetic disorders in humans is cool by itself. What made me more happy is that the paper is from a group of scientists at the Indian Institute of Chemical Biology, Calcutta, India. One of the few (AFAIK, one of the first this year) all-indian authored papers from an Indian lab in the very prestigious journal Science. (Atleast in the field of molecular biology/diseases).

Eukaryotic cells are divided into compartments: the nucleus of the cell contains the genetic blueprint of the organism (instructions coded in DNA) and is responsible for it's maintenance, expression and regulation amongst other functions. The mitochondrion, known as the "power-house" of the cell, is where energy is produced from macromolecules through a series of biochemical reactions. The mitochondria possess their own set of genetic instructions (mtDNA) which store some mitochondria-specific instructions. Mutations in the mtDNA lead to some serious disorders given that the mitochondria are the energy-centres of the cell. One such syndrome is the Kearns-Sayre syndrome (KSS) : a nervous system disorder characterized in humans by hearing loss, difficulty in swallowing, loss of muscle co-ordination and cardiac function. KSS is caused by a large deletion in the mitochondrial DNA which disrupts mitochondrial function due to loss of the information encoded in that portion.

Fixing defects in mtDNA is challenging. The mitochondria are a double-membrane enclosed compartment; delivery of material to reach the mitochondrion and get incorporated is not trivial.

This is where scientists decided to take a leaf out of the book of the protist parasite Leishmania. Leishmania is a Trypanosomatid protist parasite that is transmitted by some species of the sandfly and causes leishmaniasis ( kala azar) that is endemic to several tropical and sub-tropical countries. This group of critters are characterized by some very divergent pathways in terms of their genetic organisation. One of these includes the fact that their mitochondrial genomes do not encode any tRNA genes. (tRNA refers to a set of genes involved in the making of proteins). As a result, the entire set of tRNA genes needs to be imported from the cytosol, for which these parasites have evolved a highly specialized machinery. The transport of tRNAs from the nucleus to the mitochondria is brought about by the RIC complex (RNA Import Complex) : a mulit-subunit complex found in the inner membrane of the leishmania mitochondria. The first significant accomplishment by Adhya and colleagues was to isolate this complex and purify it. Next. they show that Leishmania RIC is capable of transporting human tRNA molecules. Then, in a series of elegant experiments described in the science paper, they went on to test if human cells are capable of taking up leishmania RIC and using it to transport tRNA molecules to the mitochondria. They incubated a variety of human cell-cultures (including cells from patients of mitochondrial disorders) with Leishmania RIC and showed that RIC was successfully localized to the mitochondria of humans. Furthermore, they showed that the defective human cells were capable of transporting a specific tRNA molecule after incorporating the RIC, which they were unable to do earlier. Thus, RIC was capable of restoring defective human cells with the required mitochondrial function, showing great promise to reverse the effects of the inherited disorder. This has great therapeutic value in correcting several defects caused by various mitochondrial mutations which are hard to reach and correct otherwise.

Think about the myriad of distances travelled here: they have crossed millions of years on an evolutionary time scale to bring a mechanism from a one-celled critter to a multicellular human system. Then, at the cellular level, crossing multiple membranes and barriers to transport molecules to the right destination. Simply fascinating!

Ref: Mahata et al, Science 20 Oct 2006 vol. 314, pp 471-474.

Biological control systems: (attempts in) Understanding the Nature's way

2006-11-12T10:58:00.000-08:00

For anyone who has watched the evening twilight, dark clouds and the flock of wild geese fly across the sky, it is not difficult to figure out the relative motion among the birds and among the clouds...even from a moving vehicle. This may seem to be such a simple everyday experience that few really think twice about it, but this is considered one of the toughest problems in image processing. Posed in a more scientific terms, the problem is how can you distinguish the relative motion between two frames in a noisy environment? Any one who has fiddled with an SLR knows how difficult it is to get a perfect picture under varying environmental conditions. A slight tremor in hand can ruin a picture. However, our eyes do it without much concious effort in part due to the excellent in built control system that exactly regulates the amount of light entering the eye and focuses the image on retina. Other aspect of the built in control system is that it corrects for the movement of the head with an interface to the vestibular organ in the ear. Such fascinating control systems are part of every biological system governing almost every aspect of life...Respiration control, blood pressure and thermo regulation, circadian rhytms, chemical reaction in cells and many more. In this article we will discuss about the light regulation system in eye and a little bit about thermo regulation.
Let there be light:
As we think about the basic parts of our eyes (Fig. 1), we observe that they consist of cornea, lens, iris, ciliary muscle, and retina connected by optic nerve to brain. Functioning of eye depends on the amount of light entering the eye (Light intensity) and focusing of the image on retina. Two independent systems control these two aspects of vision.

Source Figure 1. :http://fig.cox.miami.edu/~cmallery/150/neuro/49x6.jpg

Firstly, amount of light is regulated by the opening of pupil which is controlled by the two muscle groups in iris. Sphincter (controlled by cranial circuit which also controls the ciliary muscles which help in focusing) and dilator muscles (controlled by symphathetic nervous system of spinal cord: I wonder whether this is the reason why people look for dilated pupils when looking for vital signs in an unconcious person). Dilator muscles causes the pupil to open more whereas sphincter muscles cause the pupil to close as they contract. Acting together they control the opening of pupil in such a way that there is always an optimum light intensity falling over retina. This is a feedback control system where the pupil opening is the controlled variable( via the sphincter and dilatory muscles) while the system output is the light intensity on retina. The input is the light intensity of the environment and the control system aims to achieve a perfect pupil opening that optimizes the light intensity on retina under varying environmental conditions. By testing the pupil opening with narrow light beams (so that they do not have an effect on the light intensity regardless of pupil opening and thus disconnecting this feedback loop) it was found that the system is a very stable low gain system. Further, it is to be noted that this is not the only way eye responds to light intensity. There is another system on retina itself which adjust the signals to the optic fiber based on light intensity (reason why we can see the outlines a little better in a dark room after a few seconds of adaptation).

For more information about eye: http://www.arn.org/docs/glicksman/eyw_041001.htm

How about a little warmth as well: Maintianing optimum body temperature is vital for survival as most of the enzyme catalyzed reactions rates depend critically on it. Temperatures of cold blooded animals follows that of its surroundings (poikilothermy; one of the reasons such animals can be found mostly in tropical and temperate regions of the world) while that of warm blooded animals is tightly regulated (of course allowing for diurnal variations based on circadian rhytms) and is known as homeothermy. However, not everything is in pure black and white as is the rule in nature. During hibernation warm blooded animals such as hedgehog, bat and dormouse become coldblooded (to conserve their energy?) and this is referred to as heterothermy.
(More info on mammalian temperature regulation here: http://animals.about.com/cs/mammals/a/aa061601a.htm and Wikipedia entry:
http://en.wikipedia.org/wiki/Body_temperature )

It can be observed that for the thermoregulation system: the controlled variable is the heat producing/conserving mechanism while the output is body temperature. The input variable is the environment temperature and the temperature of the body. Now one can ask, where should be temperature be measured so that it best represents the body temperature? on the surface of the body? or closer to the internal organs? As anyone would point out, skin temperature is not the best place to estimate the body temperature, just as placing the thermometers on the outside of a building whose interior temperature has to adjusted is a bad idea. However, it is always a good idea to open/close the windows based on outside temperature while firing up the heater must be based on both outside and inside temperature. Something similar happens in our bodies too....the internal mechanism activates the heat producing/ conserving mechanism; while the case of conserving heat by closing windows regardless of inside temperature can be related to closure of sweat glands in cold weather regardless of internal temperature. This way the amount of energy expended to maintain the temperature can also be minimized. more often than not, such multiple optimization schemes are inbuilt in biological control systems.

Ref: Optimality principles in biology: Robert Rosen, Butterworths, London. 1967. [An Excellent book that deals with the issues we discussed in chapter 9]

In the next article, we hope to discuss how seemingly extremely complex branching pattern of blood circulation system can be derived from optimality arguments (again the above book has an excellent analysis).

The LISA Project

2006-11-12T09:39:00.000-08:00

The Theory of Relativity has some rather fantastic claims to make about the nature of the universe. We still find it hard to believe, for example, that time slows down relative to the rest of the universe when you travel at speeds comparable to the speed of light. Imagine then, how the scientific community at the beginning of the 20th century felt.

In 1919, British astrophysicist Arthur Eddington conducted an experiment that confirmed one of the fundamental premises of Relativity. During a solar eclipse, they measured the angle of stars behind the sun... and found that the gravitational field of the Sun did in fact bend light passing near it. From then till now, scientists have been laying out the multifarious consequences of Einstein's theory and finding ways of physically confirming them. One of these consequences is the presence of "Gravitational Waves". To the layman, one would explain it as a "wobble" in the position and shape of all matter in the universe, arising from propagating distortions caused by massive gravitational interactions like the merging of supermassive black holes or a star spiralling into a black hole.

Figure 1: The effect of gravitational waves of the two different polarizations they can exhibit: "Plus" and "Cross" (Source: Chakrabarthy, 1999)

While there do exist projects to measure the effect of gravitational waves from Earth, the quality of the data is poor. Instead of taking measurements from celestial objects, scientists want to make more direct measurements. Enter the Laser Interferometer Space Antenna, or LISA project, scheduled to be launched in the year 2015. LISA consists of three spacecraft positioned at the vertices of an equilateral triangle. Using interferometry, they can measure minute variations in their relative positions, in the range of picometers!

Figure 2: Artist's rendering of LISA (Source: NASA)

Unfortunately, such variations can be caused by a variety of factors such as solar wind, gravitational field of nearby bodies, accumulation of electrostatic charges, etc. It is an engineering challenge to develop active and passive techniques to minimize these variations in order to get an accurate measurement relating only to gravitational waves. Until the spacecraft are actually operational, it is difficult to predict how successful we will be at this.

The presence of gravitational waves is more or less accepted scientific fact, and if the LISA project is successful, it will only be the final confirmation in this regard. The purpose of LISA is much more than just confirming the nature of gravitational waves. Since gravitational waves pass through all matter whereas light and other electromagnetic variation can be blocked by various "opaque" objects, accurate measurement of gravitational waves can yield information about parts of the universe currently inaccessible to us. We would be able to settle the issue of "dark matter". We would be able to get information on the nature of the universe much closer to the time of the Big Bang than we can now. Astrophysicists are lining up issues that the measurement of gravitational waves can settle.

Since the launch of LISA is nearly a decade away, for now we can just sit back and contemplate our wobbly natures.

References:

Indrajit Chakrabarthy, "Gravitational Waves: An Introduction," arXiv:physics/9908041 v1, Aug 21, 1999

LISA Project Home Page

Wikipedia on Gravitational Waves

What is Life?

2006-11-05T06:55:00.000-08:00

As one takes an evening stroll, one can probably distinguish between all the living and non-living objects that one encounters. In spite of a classic book by Erwin Schrodinger, with a title that seems to ask one for a definition of life, published in 1943 [1], the scientific community has still not been able to come up with a single answer to this fundamental question that satisfies every scientist. Part of the reason for this ambiguity is because, to date, there remains a controversy over which objects should be considered as living beings [2]. For example, can a virus be considered as a living being?

But, first let's try to discuss some of the traits of living things:

1. Metabolism: A living being consumes energy from the surroundings by converting one form of energy to other forms of energy by a process called metabolism. Metabolism, the Greek word for change, designates all the chemical reactions carried out within a living organism.

2. Organization: The energy gained from metabolism helps organisms to remain far more organized than non-living things. Organization here refers to the fact that one can not reduce an organism into smaller independent parts. All living organisms are formed of the basic biological unit called the cell. Within each cell, there are membranes that divide the living world from the non-living world and within the membranes, the cellular constituents are organized hierarchically to form a live entity. All the molecular constituents within the cell serve a function. These molecules are organized into an integrative system and serve the activities of the cell as a whole. Some people even argue that keeping this organization going is the basic entity of life, and the minute an object is dead, this organization is lost. One can study independent parts (as molecular biology) or cells for that matter, but in reality, life as we know it, can not exist without being organized at various levels hierarchically.

3. Reproduction: Living things can reproduce on their own to produce new organisms of the same kind. The instructions to reproduce are also inherent within an organism and are inherited by each generation from their parents.

4. Evolution: Living things are able to evolve over time on their own according to their environment. They evolve due to the occasional errors that crop up while copying the instruction from one generation to another. These errors track changes in the environment and an organism that is better adapted to the environment survives. Darwin's central contention was that this adaptation stems from the interplay of random variation and natural selection. So, the history is as important as organization to understand the workings of the present day organism.

An object is traditionally considered to be living if it has all the above characteristics [3]. In addition, the definition is applied at a global level to a whole species and not to individual beings [4]. In other words, sterile organisms are also considered to be alive even though they may have lost the ability to reproduce.

Non-living things may have one or more of the above mentioned traits, but do not possess all the above mentioned characteristics. For example, a flame can use up energy and convert chemical energy to light and heat energy, using up energy in this process. However, it can not reproduce on it's own and neither does a flame evolve according to it's environment.

Viruses on the other hand are a little more difficult to distinguish. They can evolve and they can reproduce (albeit, inside another organism and not on their own), but they do not possess any metabolic capabilities, and hence, it may be argued, should be considered as not living. A small minority of the biologists have postulated that the abilities to reproduce and evolve are the only criteria for life, and that viruses should hence be considered alive.

Seeds also form an interesting example. Do we consider seeds as living or non living? Well, I did a google search and they are considered to be alive. They certainly have the ability to reproduce and, hence, evolve under the "right conditions". In addition, they are as organized as a living organism, but the real question was whether metabolism takes place in a seed under dry storage conditions. I was pleasantly surprised to find many papers reporting that seeds do undergo metabolism even during storage (an example is [5]), and hence, they do have all the criteria to be considered alive.

Physicists and chemists tend to argue over whether all the four properties are really required for life. While some chemists argue that metabolism is the real criterion for life, physicists argue that the level of organization in a cell is what really demarcates the difference between a living cell and a non-living cell. In fact, an algebraic information theoretic framework was developed to define the amount of information required to define an organism and the amount of organization in an organism [6].

What should be considered as living is not only an academic issue, but is equally important for space probes that look for signs of extraterrestrial life. In addition, it is equally important when one studies the origin of life from non-living entities. When does one consider that there is enough complexity in a system to call it a living cell? I will continue this post with a post on the quest for the origin of life and also, on a separate series of posts, on molecular evolution of living organisms.

References:
[1] What is Life? by Erwin Schrodinger.

[2] Chapters 1 and 2 of The Way of the Cell by Franklin Harold.

[3] Wikipedia entry on Life.

[4] Brittanica Encyclopedia.

[5] Metabolic activities of dormant seeds during dry storage. Naturwissenschaften, 59:3, 1972, 73-74.

[6] Toward a Mathematical Definition of "Life" by Gregory C Chaitin.

In Living Color (Part 1)

2006-11-02T04:23:00.000-08:00

This is the first in a series of posts that will describe how light and optical technologies are playing an important role in modern biological investigations. This post is about fluorescent proteins, their history and some applications.

It is often said that the 21^st century will be (is) the age of biology; much like the previous century was for physics. New discoveries are occurring and biological information is growing both in size and complexity at an exponential rate. A major factor fueling this growth is the plethora of technologies available to the modern biologists in their quest to uncover the very basic molecular mechanisms of life.

Among such tools, the discovery and use of fluorescent (light emitting) proteins, has proved to be a major boon for scientists investigating activities of genes and proteins inside cells. Fluorescence is an optical phenomenon, where a molecule absorbs photons of a particular color and thereafter emits photons of a different color - with the emitted color always red-shifted. While this phenomenon had been observed in living organisms, the molecules involved in the luminescence were unknown till the 1960s. In ‘62, Osamu Shimomura, a Princeton scientist investigating the phenomenon of bioluminescence, isolated a light-emitting protein from the jellyfish, Aequorea victoria, in the Padget Sound area of Washington state. This protein, named aequorin¹, produced blue light – but only in presence of calcium. However, as a footnote in the publication of this discovery, Shimomura and co-worker mentioned “….a protein giving solutions that look slightly greenish in sunlight through only yellowish under tungsten lights, and exhibiting a very bright, greenish fluorescence in the ultraviolet of a Mineralite, has also been isolated…”. It was soon found that this ‘other protein’ was involved in absorbing the blue light from Aequerin and emitting the green light observed in the jellyfish. It was named appropriately, even if perhaps a little unimaginatively, the green fluorescent protein (GFP).

The jellyfish, Aequorea victoria, on the left and green bioluminescence observed around the margin (note the picture on the left does not show fluorescence !)

However, it took another thirty years before the GFP became the almost ubiquitous cellular and molecular biology tool it is today. In 1987, Doug Prasher, then at the Woods Hole Oceanographic Institute, discovered and was able to make a copy of the DNA sequence within the jellyfish gene that encoded for GFP. He did not, however, succeed in making a glowing protein from the DNA sequence in the lab. Subsequently, Prasher sent his sequence to a researcher at Columbia, Marty Chalfie who was able to produce the protein in bacteria - a typical trick used by biologists to make proteins. As shown in the figure on the right from Chalfie's work, the bacteria containing the genes for GFP (on the right side of the plate) emits green light under illumination with ultaviolet lamp (it was a graduate student doing rotation in Chalfie’s lab that actually performed the work and made the discovery!). This seminal work, published in 1994 in the journal Science, led to 'an explosion of color' in the biological world. Subsequently, other researchers showed that the GFP could be produced, alone or in tandem with other proteins in a variety of organisms.

Over the last decade, a great deal of research has contributed towards understanding the underlying physical mechanisms of GFP’s light emission² and importantly, towards improving its properties through genetic manipulation. The leader in this field has been Roger Tsien, who along with co-workers demonstrated that making small changes, such as replacing a few amino acids in GFP could make it glow brighter, mature faster and prevent aggregation of the protein inside cells. His group has also succeeded in tuning the absorption and emission of the original GFP through mutagenesis, leading to a veritable palette of fluorescent proteins that absorb and emit light through the entire span of the visible light spectrum (see below). Additionally, a Russian scientist, Sergey Lukyanov, used the GFP sequence as a 'bait' to search for novel fluorescent proteins in corals and succeeded in finding several GFP-like proteins, particularly a red-emitting fluorescent protein, dsRED from Anthozoa, which is also used widely.

Panel on top shows the fluorescent protein 'palette' developed by Tsien lab - note range of colors and the fruity names. On the left, artwork with bacteria expressing various colors of fluorescent protein.

The major advantage of GFP is that inside a living cell, it can emit light on its own without the help of another protein or other chemicals. It is also possible by using molecular biology techniques, to attach the DNA of GFP to the DNA of the protein of your choice to produce a recombinant DNA. When the information from such recombinant DNA gets translated into a protein within the cell, a tandem protein is created with the GFP unit hanging from the protein. Importantly, since the size of GFP is relatively small, in most cases it does not interfere with the regular functions of the protein it is attached to.

In the simplest of applications, after shining light on the cells, the total amount of fluorescence obtained from the cells provides a measure of the level of expression of the protein tagged with GFP. However the more useful applications involve cells placed under microscopes with high magnifying power (40x to 100x) in conjunction with either arc lamps or lasers for bright illumination and high-resolution detection devices such as CCD cameras for
capturing images of the emitted light. In these cases, we can literally see where the protein of interest is located, or illuminate a particular subcellular structure. For example, the figure on the right shows the mesh of protein network that act as a 'skeleton' (in fact it is called the 'cytoskeleton') in majority of cells in higher organisms. A protein called 'actin' that is involved in this scaffold has been tagged with GFP.

It is also possible to tag two or more proteins in the cells with different fluorescent colors (see the fluorescent protein palette above) and follow their localization or movement in cells. This helps in noting where two proteins are localized during a cellular function. In the figure to the right, the protein actin is now tagged with a cyan emitting fluorescent protein (CFP). Another protein, vinculin, has been tagged with a yellow fluorescent protein (YFP). You can observe that the YFPs are localized as small elliptical structures at many places. These are called focal adhesions, which form a link between the cell cytoskeleton (in cyan) and its extra-cellular matrix. This interaction help cells to adhere and eventually move about in a tissue.

(in a future post, I will talk about a technique involving fluorescent proteins of two colors which is used to determine if two proteins interact with each other inside a cell)

Perhaps the most powerful application of fluorescent proteins is when you combine microscopy with time lapse video images. In such cases, it is possible to observe where and when the translocation of the protein in cells is taking place under a biological condition. For example, see a video here of a cell moving around with a protein involved in the focal adhesion tagged with GFP.

Visualization of protein location and dynamics in this manner enable scientists to place cells under various physiological conditions and observe the resultant phenotype of the protein behavior. Before the advent of GFP, scientist had to destroy the cells and use other tedious biochemical techniques to obtain similar information. Even then real-time data acquisition was not possible.

A quick search of the database will reveal more than ten of thousands of peer-reviewed publications where fluorescent proteins have been used to study protein functions at the cellular level. In most of these cases, research was conducted with either unicellular organisms or cells derived from tissues of mammals. However, apart from single cells, fluorescent proteins are also being used at the tissue and even the whole organism level. The picture below shows an example of a research which is investigating the movement of neurons (labeled with GFP) in the cerebral cortex.

A more well-known example of GFP in whole organisms, is the development of 'fluorescent mice' by the company Anticancer Inc . It is easy to follow tumor progression and cancer metastasis in such mice. Also, a Taiwanse reasearch group recently created 'fluorescent pigs'. Stem cells or organs from these pigs when transplanted into other organisms can be followed easily without requiring invasive techniques.

Animal Farm: fluorescent pigs and mice.

More examples of such applications of GFP can be found her e. Apart from these animals, 'Alba' , the fluorescent rabbit and fluorescent aquarium fishes are two examples of more esoteric application of this scientific technology.

On a final note, betting markets for the Nobel Prize (yes they do exist !), were predicting this year’s Chemistry Nobel to go to Roger Tsein and others for their work on fluorescent proteins. It eventually went to Roger Kornberg for his work on DNA transcription. Considering the importance of fluorescence proteins and their wide-ranging revolutionary impact on biology, it is not far-fetched to think that the Nobel is not beyond the grasp of these researchers.

Notes:

1. Aequorin itself has been very useful for visualizing cellular calcium concentrations, the regulation of which is important for a number of physiological activities.

2. Without going into great details about physi-chemical mechanisms of GFP fluorescence, suffice to say that the protein has a barrel-like structure (see below); within the barrel, three critical amino acids are brought together in close spatial proximity, which forms the chromophore.

Artistic rendition of the three-dimensional structure of GFP.

3. All images have been linked back to their original web-page.

4. Recommended further reading: This web-site is a very good resource for learning more about GFP's discovery, structure and applications. Also read this interview with Dr. Martin Chalfie.

Coming up: "Much to fret about ": on a technique known as fluorescence resonance energy transfer that enables biological distance measurements, detection of protein interactions, and can be used to look at protein functions at a single molecule level !

A Splicing Primer

2006-10-25T07:19:00.000-07:00

The central dogma of molecular biology DNA-> RNA-> Protein shows the direction of flow of information of how the cells use the information stored in our DNA to make the necessary proteins. But the situation in most eukaryotes is a little more complex than that simple statement. In most eukaryotes, a gene sequence in a DNA is interrupted by non- coding information. Hence to make a protein, a cell first has to transcribe the gene (make a RNA copy of the gene, called pre-mRNA) and then modify the pre-mRNA by removing the non-coding sequence (intron) and joining the coding sequences (exons) together. The modified mRNA is then exported from the nucleus (where it was made) to the cytoplasm where the ribosome uses it as a template to make the protein. In simple English, the gene for making a proteinA looks like this "HEREabhjhdyfrhUSEndcbldfhdfmMEd ldshhglgmcFORdbfhdflhfnmc PROTEIN A". The task of the cells is to remove the gibberish and make a readable text out of the given instruction - HERE USE ME FOR PROTEINA. The cells then send this information to the ribosome (the protein factory) to make the protein.

Pre-mRNA splicing is the process in which the intronic sequences are removed within a large RNA-protein complex called spliceosome.

Why is splicing important? A spliceosme can remove the non-coding introns present in a given transcript varying combination in response to cellular cues, a process called alternative splicing. The recent completion of a draft of the human genome indicated that more than 59% of the human genes seem to be alternatively spliced (Hastings and Krainer,2001) and thus we can have more complexity (make a larger number of proteins) without increasing the number of genes present. For eg, the Dscam gene in flies has 38,000 alternatively spliced isoforms from four variable exon clusters!
More importantly, it is estimated that aberrant splicing causes about 15% of genetic diseases in humans (Philips and Cooper,2000). Thus, the spliceosome plays a critical role in generating the right template for making a protein and any abnormality in this process would be deleterious to the organism.

What do we know about this process? From genetic and biochemical experiments in the humble budding yeast, scientist have been able to understand how this process occurs. Because both the mechanism of splicing and the splicing machinery are highly conserved throughout eukaryotes, knowledge of yeast splicing gives us insights into the basic process in humans.

The spliceosome is the largest structure in the cell and is composed of five small nuclear RNAs ( called U1, U2, U4, U5 and U6 snRNAs) and over 100 different proteins (Stevens and Abelson , 2002). Under standard in vitro (i.e. in a test tube) assay conditions, the spliceosome assembles in a step wise manner through the addition of the U1 -> U2-> U4/U6.U5 snRNP particles (the small nuclear RNA along with its associated proteins, represented by a colored blob in the picture) on the pre-mRNA (See Figure). This assembly is an expensive process for the cell as each step consumes energy. But it also allows the apparatus to check each step and hence allows for a greater control over the overall process. Remember, a single mistake here would result in a protein that either does not function or functions abnormally. That to a cell would be hazardous and hence the cells err on the side of caution. After the assembly of the spliceosome, it undergoes structural rearrangements, resulting in the loss of U1 and U4 snRNAs, to become catalytically active (Brow D. A, 2002). Then, it proceeds to remove the intron by two transesterification reactions.

The resultant message is released from the spliceosome along with the intron. The spliced RNA is exported to the cytoplasm for translation into the protein and the intron degraded by enzymes in the cell. The spliceosome is disassembled and the components (proteins and the snRNAs) recycled for another round of splicing.

Though much is known about the overall process, there is no insights into what triggers the activation. What informs the spliceosome that everything is set in place and hence go ahead and splice? How does the cell control the ATP driven helicases that remodel the spliceosome at each step? Or what cues the cell about abnormal spliceosome and how does it take a stalled spliceosome apart?

Next time I will try and address the role splicing plays in Humans. How does a cell choose which exon to keep? How do DNA elements present in the gene (ISEs) affect choice of exon? Does the rate at which the transcript is made affect exon choice? So keep your eyes out for Splicing -part deux.

References -
Brow D. A, Annu Rev Genet., 2002, Jun 11; 36:333-60.
Hastings and Krainer, Curr Opin Cell Biol., 2001, Jun; 13(3):302-9
Philips and Cooper, Cell Mol Life Sci., 2000, Feb;57(2):235-49
Stevens and Abelson , Methods Enzymol. 2002;351:200-20.
Check this Animation

A Beautiful Mind

2006-10-14T12:32:00.000-07:00

"Imagine if you'd suddenly learnt that the people, the places, the moments most important to you were not gone, not dead, but worse- had never been. What kind of hell would that be?". - A Beautiful Mind, 2001.

I saw the movie for the second time last night and it got me thinking about the complex disorder that is schizophrenia, and the intense effects it has on an individual, making him lose the distinction between real and imaginary. So what is it that makes a person harbour irrational thoughts and so convinced about the his false fears? I tried to poke around the literature to try to understand how much of the organic basis for this disorder is understood. There is the genetic component- the heritable nature of this disorder has been well documented over the years. Mutations in genes that are involved in brain function can be inherited, causing offspring of schizophrenics to be that much more at risk of developing the disorder. The environment plays an equal role, stress and psychological trauma are known to have a causal or triggering effect in schizophrenia, translating genetic predisposition to development of the disorder.

The neuropathology of the disease itself is closely linked to the above described factors. Bad genes, as well as early trauma to the brain, prenatal exposure to infections and psychological trauma result in brain abnormalities that cause cognitive defects and result in the disorder. There are two aspects to understanding how impaired brain function leads to this condition. Firstly the anatomic location of neural systems that are disrupted govern the types of symptoms exhibited by a patient. Various regions of the brain are involved in different functions such as processing impulses, perceiving thoughts and producing a reaction to a stimulus. The distortion in reality observed in schizophrenics is attributed to one region of the brain, thought disorganisation involves malfunction of a different circuit, while a decline in perceptive and physical responses are traced to malfunction in yet another circuit.

Secondly, brain chemistry- in terms of fluctuations in neurotransmitters (the chemicals that transmit signals in the brain cells) control the duration of above mentioned symptoms, to add another layer of complexity to this intricate orchestration. The sum effect of all of this is disorganised thinking, delusional and paranoid thought processes and auditory hallucinations that manifest as schizophrenia.

Dopamine, glutamate and NMDA are some of the neurotransmitters that have been implicated in schizophrenia. The "Dopamine hypothesis" is particularly famous, as it was one of the first major biological causes that could be attributed to schizophrenia. However, it is now thought to be an oversimplification at understanding the disorder, since there are other factors that play a role. Nevertheless, I will discuss the hypothesis because it provides atleast some insight into the process, and is quite fascinating.

Dopamine is a neurotransmitter, and in one of it's functions it is associated with the "pleasure system" of the brain, providing feelings of enjoyment and motivating a person proactively to perform certain activities. Essentially, it mediates the conversion of an outside stimulus from being a "cold" or neutral bit of sensory information into an "attractive" or an "aversive" entity.

For example- normally an external stimulus such as a bright red sports car zipping past a pedestrian might result in a surge of dopamine to cause an appropriate reaction- like the pedestrian turning his head to look at the car. However, the reaction elicited also depends upon the the pedestrian's predispositions and experiences. A race-car enthusiast may turn to look, while a person not interested in sports cars will not exhibit any reaction. In any case, dopamine here mediates a contextually relevant reaction.

In the 1970s, it was discovered that drugs that block dopamine function reduced psychotic symptoms. Further studies led to the hypotheses that dysregulated dopamine transmission causes an abnormal release of dopamine, so that what would have been a normally neutral stimulus results in firing up of neurones and causes aberrant reactions to external objects or their internal representations. Remember Nash in the movie reacting to something as simple as his wife turning on the light by saying "Why did you turn on the lights? Why would you do that? Why?" ?

In this stage, the patient develops a sense of anxiety and confusion, and an intense need to make sense of the new "realities" being experienced. Any and every normal occurrence can produce an exaggerated response in his mind, and he keeps looking for meanings and explanations to calm himself down. As he forms delusions in his mind to explain the occurrences, he experiences a feeling of relief and reduced perplexity. These delusions then persist, even after the stimulus is taken away, eventually taking on a life of their own. Hallucinations arise from similar aberrant thought processes, as the patient conceives an incorrect internal image of a thought or a memory that is percieved and reinforced with such intensity as though it were real.

This is, like I said earlier, just one aspect of cause and development of psychoses but enough to give us a peek into the on-goings in the brain of a schizophrenic. Imbalances in other neurotransmitters and pathways have different ways of interfering with normal thought process and causing psychological disturbances. Given the limited knowledge and understanding of this disorder, how is it brought under control?

Anti-psychotics are useful in the treatment of psychoses, because, in one way, they dampen the effect of the excessive dopamine (in this example) and thus restore a chemical balance that calms the patient. However, they do not change the underlying thought process- all they can do is prevent neutral stimuli from producing abnormal reactions, and quenching aberrant reactions produced initially. Thus, patients are able to "ignore" or control their reactions to stimuli, but are not entirely free of the delusional thoughts that have already formed. This underscores the importance of staying on the drugs as long as is necessary, and also protecting the patient from high stress environments that can cause a resurgence of symptoms. Modern drugs are now being developed to limit side-effects in patients. Imaging technologies have improved to better visualise brain abnormalities associated with schizophrenia. With the availability of genome sequences and better tools, more genes are being discovered that may play a role in the disorder. Emerging tools in pharmacogenomics can make the best of these discoveries to improve treatment. Social acceptance and sensitivity towards the ailment is also needed , to create a support system that does not stigmatise patients.

John Nash's story is a very encouraging one in the face of this complex disorder. His story shows that one can be successful in bringing the disorder under control to a large extent. Eventually, Nash learns to ignore his irrational fears and focus on his passion. The same brain that gave rise to abnormal thought processes also contributed to his Nobel-prize-winning work on the game theory. Indeed, the mind is a beautiful thing!

References: 1) Wikipedia
2) Schizophrenia: challenging the orthodox McDonald et al
3) Schizophrenia in a molecular age. Carol A Tamminga

How does a digital camera work?

2006-10-09T21:37:00.000-07:00

In the previous post, I had talked about how a digital photograph is stored in the computer. In this post, I will talk about how a digital photograph senses the photograph talking only about the essential components (using description for RGB colors). A modern digital camera has far more advances than the simplistic picture explained here.

A digital camera has a number of lenses which focus light onto chips that are sensitive to incoming light. In the market, there are two types of image sensors - charge-coupled device (CCD), and the Complementary Metal Oxide Semiconductor (CMOS). CCDs [1] are far more popular than CMOS chips because they are considered to be affected by noise to a lesser extent (and I will use CCDs to explain how a digital camera works). The role of this chip is to sense the light that comes in and convert the light energy to an electric signal that is amplified and then digitized and finally processed.

How a CCD works? Photoelectric effect [2] is the property by which some metals emit electrons when light shines on them. The CCD in the digital camera is a silicon chip that is covered with a grid of small electrodes called photosites. One photosite corresponds to each pixel.

Before a photo is taken, the camera charges the surface of each photosite with electrons. When light strikes a particular side of the photosite, the metal at that site releases some electrons, which travel to the opposite end of the site (forming what is commonly called the capacitor). The larger the intensity of the light that falls on it, the larger the number of electrons that are released, and hence larger the voltage that develops across the photosite. The voltage is then converted to a number using an analog-to-digital converter that corresponds to the intensity of the light that falls on that site. This takes care of the intensity, but we have not discussed about how the photosite knows the color of the light.

As discussed earlier, the color of a pixel is formed by mixing red, green, and blue colors (RGB). So all the light does not hit each photosite, but rather, there is a filter placed on top of the photosite that only lets red, green, or blue color through. Hence, depending on what color is through, each photosite only measures the intensity of the red, green, or blue color that falls on it, and no other color. After this, to measure the intensity of green and blue colors on a site with a red filter, an interpolation algorithm (a process called demosaicing) is used that approximates the intensity of the blue and green light on that site using the intensity of these colors in the neighboring sites.

Lastly, as green is in the center of the spectrum in the visible light (VIBGYOR), our eye is better at picking up different shades of green, and hence, there are a larger number of photosites that sense green light than blue or red. The Bayer pattern shown below is the most common arrangement of photosites in a single array CCD chip.

The other end of expensive digital cameras (read 10's of thousands of dollars) have multiple arrays and avoid the interpolation step. So the incoming light could be split into three copies and then passed through three separate filters and three different arrays and sensed separately to make the final picture by merging these readings together.

There are more complications that arise even in the simple camera, but maybe another post to deal with them (but no promises as I got to do some research before I can post myself).

[1] CCDs were invented by George Smith and Willard Boyle at the Bell Labs.
[2] Albert Einstein won the Nobel prize in 1921 for the quantum explanation of photoelectric effect.

Source:
The source for most of this stuff is Chapter 2 of the Third Edition of the Complete Digital Photography by Ben Long, though the mistakes here are probably mine.

For further reading:

How Stuff Works answers how a camera works
How an image sensor works?
CCD vs CMOS
Wikipedia's CCD entry

How is a digital photo stored?

2006-09-29T12:00:00.001-07:00

Just as the word digital suggests, a digital camera digitizes every image that it captures. What this means is that a typical rectangular photo is divided into a large number of squares which form the basic picture element called the pixel. Within a given pixel, the color of the image does not change. In the simple case where the pixel can either be black or white, the state of the pixel can be binary - either 0 (white) or 1 (black). The state of each pixel is stored at each location and when all the pixels are put together, you get your image back. Hence, the image is said to be digitized now.

In the real world, most pictures are stored either in color or in various layers of grey scale. For example, when each pixel element is stored as 8 bits, the number of states would be 256 - a number from 0 to 255. 0 represents white, 1 to 254 represents various scales of grey in increasing intensity, and 255 represents black. So when a color photo taken with a digital camera is converted to black and white, the correct term is actually a grey scale photo, because it has varying levels of black and white.

In color photographs, each pixel is made by combining various levels of primary colors. When an artist mixes colors with paints, he combines 2 colors to make a 3rd color. The primary colors are the colors which can combine to make all the colors required in a digital camera. In a typical camera, the primary colors used are Red, Green, and Blue (forming the RGB colors). Another set of primary colors used often are Cyan, Magenta, Yellow, and the Black (called the CMYK colors). Each color set has it's own advantages as it can capture a certain range of colors well. The rest of the post will be based on a RGB photo though it will equally apply to CMYK or any color set.

In the case of a RGB photo, each pixel uses up three storage units (for each color) of certain bit size associated with it. In the case of the 8-bit size storage unit, each pixel will have one storage unit each for intensity of red color (numbers 0 to 255 signifying varying levels of red color similar to the grey scale pictures discussed above), green color, and blue color. The various levels of red, green, and blue colors are mixed to form the actual color of that pixel. A picture stored in this manner would be 24-bit picture because each pixel would be stored in a 24-bit memory unit. The fact that the color of a pixel does not vary can be seen when you blow a picture beyond 100%. When the picture on the left is blown up to look at each pixel, the picture will look as the one on the right:

(Picture courtesy http://photo.net/equipment/digital/basics/)

The larger the resolution of the picture, the larger the number of pixels per inch (PPI). If one were to print a photo on paper, the resolution should be greater than 200 PPI on each side of the rectangle. A 3 MP camera can hence be used to print out photos of the 4" * 6" prints. The greater the resolution of the camera, the larger the size of the photo that can be printed out from it.

I will follow this post with a post on how the digital camera senses each photograph.

To get more information on this:
Photo.net's tutorial
Cambridge's tutorial

Living in a distributed world

2006-09-27T18:31:00.000-07:00

In this post I had mentioned how ants work together to find a short way past obstacles, and said that they are not the only living things that work in that way. Engineers, though, have a different way of looking at it than pure scientists. These types of systems are called Distributed Control Systems, meaning that there is no central controlling authority, but instead, each individual follows a set of simple rules and this alone is enough to achieve the system's objectives.

Such a concept may seem alien at first. We humans are used to a hierarchical system of getting things done... in governing citizens, in managing corporations, in controlling manufacturing systems, in practically everything, we have a system of smaller parts reporting to progressively larger parts. But there is evidence to show that simple rules followed by a large number of peers can lead to as complicated a global behaviour as might be required.

I'm going to take an example of a non-living thing this time. The following experiment is called Conway's Game of Life. Consider a two dimensional matrix, in which each cell can have a state of "dead" or "alive". Each cell has eight neighbours; if zero or one of them are alive, the cell dies of loneliness. If two or three neighbours are alive, the cell lives. If four or more neighbours are alive, the cell dies of overpopulation. A dead cell "comes to life" if it has exactly three live neighbours.

Depending upon the initial state, an astounding variety of beautiful and complex patterns have been observed to arise out of these simple rules, including different types of oscillators, explosions, firing guns, even moving spaceships!

A snapshot of the Game of Life Applet: From http://www.ibiblio.org/lifepatterns/

While I used this only to demonstrate that simple rules can result in complex, self-organizing behaviour in a distributed world, the fact remains that a lot of the "management" in nature occurs this way. It doesn't take an engineer to understand the problems with centralized control in a large hierarchy; if you've tried getting something past the bureaucracy of your university, workplace or government, you know it all too well yourself! But engineers understand how difficult it is to design a distributed control system. It is only in extreme circumstances that they do indeed deploy systems in such a manner - for example, in large sensor networks, where thousands of sensor nodes may be released in forests, underwater, anywhere!

We live in a distributed world, in which the sum of parts is inevitably greater than the whole. Sometimes we scientists get a glimpse of it in our computer simulations, but you only need to look out of your window to understand. When you see a flock of birds flying in formation. When you see a beehive. And once you truly understand it, you will see the world through brand new eyes.

X Chromosome Inactivation

2006-09-25T05:35:00.000-07:00

That cute kitten is Copycat or CC – the first cloned cat. She is genetically identical to her “mom” (to the right) but phenotypically different. The reason is because of the peculiar phenomenon called X-chromosome inactivation (XCI) that occurs in all the female cells in mammals.
In mammals sex is determined by differential inheritance of the sex chromosomes. Females are XX while males are XY. To compensate for having an extra dosage of X chromosome genes that might be developmentally fatal, the cells in the female embryo randomly select one X chromosome and shut it off (transcriptionally silence it). This “silent” state is maintained throughout life in the female cell. Since the phenomenon is random (each cell independently decides its fate), mammalian females are essentially mosaics. CC is different from her progenitor because the gene for coat color lies on the X chromosome and is randomly silenced in the clone, giving it it’s unique calico pattern.
The phenomenon is evolutionarily conserved in the mammalian lineage – since there is preliminary evidence to suggest that XCI occurs in Prototherians (egg laying mammals) who arose 200-300 million years ago and also in Metatherains (marsupials). Since X and Y differentiation also occurs in these lineages, it is likely that XCI arose as a way of dosage compensation.
How is it done? The random X chromosome inactivation has been linked to a region on the X chromosome, called Xic (X- inactivation center). What is so unique about this region is that all the genes characterized so far are non- coding genes – they make the RNA but this RNA is never used to make a cellular protein. The ncRNA (non coding RNA) from this region are responsible for counting the number of X chromosomes present in the cell, marking one for silencing and maintaining the silenced state. The most talked about transcript from this region is Xist which is essential for the silencing step.
The mechanism of how the ncRNA form Xist or other mapped locus do the inactivation is not yet known. It is most likely that transcription of these genes help to bring in chromatin remodeling factors (things that signal that the chromosome is silenced). Since Xist transcription would take about 30 minutes, during which the RNA is physically attached to the X chromosome, this explanation seems plausible. The unraveling of the mechanism would help us understand another dosage compensation mechanism (that of imprinting) but that is another blog.

Learning from the humble ant

2006-09-23T13:05:00.000-07:00

The next time you're outdoors and you see a trail of marching ants, try a little experiment. Place an obstruction asymmetrically in their path, which is steep enough that they can't climb over it, and see what happens. At first, they would spread out equally in both directions to rejoin the trail. Over a period of time, you'll see the longer trail thin out and disappear as all the ants start taking the shorter trail.

What's really remarkable about this is that ants cannot see and cannot talk. That is to say, they lack the sensory organs for sight and sound. So how do they do this job of finding a short route around obstacles to their target food source?

The secret, as with many other things observed in nature, is elegant in its simplicity and inventiveness. Ants have a very good sense of smell, and lay out a class of chemicals called Pheromones to mark their trail. Each ant lays out roughly the same amount of pheromone for a particular food source, and the pheromone evaporates at a constant rate. When an ant moves towards a marked food source, it tends to move in a direction in which it senses a relatively higher concentration of pheromone.

That's all. If you're puzzled as to why I cut the explanation short, take a minute to think about how this would work and then read on. Now, when the obstacle is placed in the path, the ants can no longer sense the correct direction to travel, and they choose at random among the available directions. Ultimately, they would rejoin the trail, but each ant has now laid pheromone along the path it has taken. Initially, there is little to choose from between the two options, but over a period of time, the shorter path, simply by virtue of being shorter, would have a greater number of ants traversing the path back and forth. This means that the evaporating pheromone on the shorter route gets regenerated more often than on the longer route, causing more ants to choose that direction over the other. This further increases the disparity in pheromone level between the two choices, until there is insufficient pheromone on the longer trail to tempt even a single ant to go in that direction.

This kind of a process is called Auto-Catalytic, meaning it speeds itself up. Some time around 1990, an Italian scientist called Marco Dorigo got a brainwave on how to use this ant behaviour to solve combinatorial optimization problems, which are notoriously difficult to solve with conventional mathematical techniques.

What he did was to represent an optimization problem as a set of obstacles in the path of an ant trail. The decision of which direction to take at an obstacle represented the decision of what value to assign to a variable. In other words, if a variable can take four different values, it is like placing an obstacle giving an ant four different paths around it. Each variable in the problem is equivalent to an obstacle on the trail. "Pheromone concentrations" are maintained virtually for each decision at each obstacle.

The generation of a solution is done randomly, with the probability of taking a particular decision being proportional to the virtual pheromone concentration. Then, the "goodness" of the solution is quantified by the objective function, and this is analogous to the distance traveled to reach the food source by that route. If it is a poor solution, it is a long route and the pheromone concentrations along that route are increased by a small value. If it is a good solution, the pheromone concentrations are increased by a higher value; and all the time, pheromone is "evaporated" at a constant rate at every decision point.

It worked. In a way similar to how ants find paths, an algorithm known as Ant Colony Optimization (ACO) was developed and refined, and although it does not always find the globally best solution, it tends to find a good solution for even large problems in reasonably quick time.

In spite of all the nature-defying technological marvels scientists and engineers come up with, there seems to be an infinite depth to the workings of nature from which we learn continually. The ant optimization algorithm is but one in a wide class of algorithms under the banner of Swarm Intelligence, for ants, bees, birds and many other social denizens of nature have unique and innovative ways of doing a plethora of tasks. Computer scientists observe, and come up with smarter algorithms. Engineers observe, and come up with better control system schemes.

How wrong we are, in talking about "humble ants". It's we who are the "humble scientists".

Links for further reading:
Marco Dorigo's page on the behaviour of real ants that inspired ACO
Wikipedia
Marco Dorigo's landmark paper on Ant Systems

About us

2006-09-23T08:00:00.001-07:00

TGFI has always been fascinated by two areas of science the most, astronomy and biology. Over time, the double helix has won her over and she decided to get a Ph.D in molecular biology way back when she was in high school. Fundamental processes in which genes operate, regulate and interact within a system fascinate her the most, which also happens to be the area in which she is getting her Ph.D. Five years at it and she realises how hard it has become for her to think outside her little world. Which is why she think this collaborative blog is a great idea, will make her get out of her world a bit, and talk about science in layman's words. She hopes to contribute on here once a month.

Sakshi is a grad studnet in UK and work on splicing and spliceosome assembly in the budding yeast. Her project focuses on how a cell targets misformed or locked spliceosome and activates turn over. Her interests in science lies in molecular / genetic underpinnings of life. Though she makes frequent forays into other aspects of biology, she is interested in regulation of gene expression (she believes RNA to be the coolest thing, ever). To keep her sanity in the ever crazed world of an underpaid, over-worked graduate student, she indulges in photography, reading (she prides herself on reading everything she can lay her hands on) and listening to music or watching movies.

Prashanth is an incurable romantic and an incorrigible geek from Chennai who tries to convince himself that they are both desirable qualities. He can be bribed into doing almost anything by lending him a good book. He is currently doing his Ph.D. in Industrial Engineering at the Pennsylvania State University.

Murthy is a grad student (and an engineer by birth) who is interested in many things some of them being: Control systems application to biological systems and control systems in nature(They are more interesting and far more elegant than the crude imitations scientists try to build and feel proud about). Algorithms and coding, Fluid mechanics and ofcourse Biology, specifically immune system of mammals and behavior of microorganisms as influenced by evolution are all part of his scientific interests. He is an Agricultural engineer(Specifically Dairy, food Engineer by training) now working in biofuels and control systems.

Back in high-school, BioPondit was aiming to be an engineer, loved physics, but ended up with a undergraduate degree in chemistry. Continuing in this vein, he trained as a Biophysicist in graduate school and is currently engaged in post-doctoral research in Cell Biology, shedding light on cellular signaling mechanisms. Love of books, cinema and an esoteric taste in music is what drives him - that and an ice-cold martini (stirred not shaken). A desire to communicate the beauty of science is what brings him here.

BaL is a grad student in the Chemistry department at the U of I. Broadly, he works on Computational Biophysics, Bioinformatics, and Evolution and these interdisciplinary fields keep him on his toes most of the time. He is also fascinated by cricket, movies (both Hollywood and Bollywood), and photography. He also tends to listen to a lot of desi music (especially Rehman), and classic rock.

Sonya is and always will be a science dork. Since a very young age, she has been fascinated by animal behavior of all aspects. She has long been amazed with how interactions within species, as well as, across species are affected by evolution and how they often eventually lead to speciation events. Although she believes that studying behavior in a natural environment is important, she is now more interested in how neuronal control (neuromodulators) may affect behavior. It is with this goal in mind, that she is working on her Ph.D in a Neurophysiology lab at University of Kentucky and currently working on understanding physiological mechanisms that may influence behavior in invertebrates. Since she is very engrossed in the early stages of her projects, she does not have things to keep her sane. You may on any given day find her talking to her crayfish..luckily they haven’t started talking back yet.

Curious Cat is a theoretical physicist. Her chosen tools of trade include non equilibrium statistical mechanics (the pen and paper kind) and her focus is the dynamics of fluids and fluid-like systems. She is currently post-doc-ing in the New York and Boston area. But this is just the way she earns her bread so to speak. She likes to read widely outside her area of specialization and likes to reduce all that information into minimum models that are easier to understand but still contains the essential features of the true science of the system. And that is why she is a physicist, becuase it gives her the training to be able to do that. She blogs about this and that at http://virtualcuriosityshop.blogspot.com. You can see the few physics posts she has written so far on this blog as well.

About this Blog

2006-09-17T20:20:00.000-07:00

This blog is an attempt to answer any questions we have in mind such that an high school graduate should be able to understand the fundamentals behind the scientific ideas. It could also serve as a portal for us to broaden our knowledge on a subject. The topics that will be discussed will be from a wide range of topics dealing with basic science, and technology. This blog will hopefully be a learning experience for us and it will also be a medium through which we can share our knowledge with each other and with any person who is interested in these topics.