Interesting Quotes

Over the course of my perusings amongst various soft science books, I've kept a record of some of the interesting quotes I've come across. Here they are.

"To begin with, for you to be here now trillions of drifting atoms had somehow to assemble in an intricate and intriguingly obliging manner to create you...Why atoms take this trouble is a bit of a puzzle. Being you is not a gratifying experience at the atomic level. For all their devoted attention, your atoms don't actually care about you- indeed; don't even know that you are there. They don't even know that they are there. They are mindless particles, after all, and not even themselves alive. (It is a slightly arresting notion that if you were to pick yourself apart with tweezers, one atom at a time, you would produce a mound of fine atomic dust, none of which had ever been alive but all of which had once been you.) Yet somehow for the period of your existence they will answer to a single overarching impulse: to keep you you." - Bill Bryson

"They [atoms] are also fantastically durable. Becasue they are so long lived atoms really get around. Every atom you possess has almost certainly passed through several stars and been part of millions of organisms on its way to becoming you. We are each so atomically numberous and so vigorously recycled at death that a significant number of our atoms-up to a billion for each of us, it has been suggested-probably once belonged to Shakespeare. A billion more each came from Buddha and Genghis Khan and Beethoven, and any other historical figure you care to name." - Bill Bryson

"You can get some idea of the proportions [of atoms] if you bear in mind that one atom is to the width of a millimeter line as the thickness of a sheet of paper is to the height of the Empire State Building." - Bill Bryson

"As Cropper has put it if an atom were expanded to the size of a cathedral, the nucleus would be only about the size of a fly- but a fly many thousand of times heavier than the cathedral." - Bill Bryson

Richard Feynman once observed that if you had to reduce scientific history to one important statement it would be "all things are made of atoms." - Bill Bryson

"The early morning’s thinnest sliver of light appeared silently. Several billion trillion tons of superhot exploding hydrogen nuclei rose slowly above the horizon and managed to look small, cold and slightly damp." - Douglas Adams

"Consider one microgram of table salt, a spack just barely large enough for someone with keen eyesight to make out without a microscope. In that grain of salt there are about 10^16 sodium and chlorine atoms. This is a 1 followed by 16 zeros, 10 million billion atoms." - Carl Sagan

"Chlorine is a deaadly poison gas emplyed on European bttlefields in World War I. Sodium is a corrosive metal which burns upon contact with water. Together they make a placid and unposionous material, table salt." - Carl Sagan - Broca's Brain

"Francium is the rarest element on the planet. At any given time, it is thought, that only 15 atoms of it exist on the planet." - Bill Bryson

"Carbon is shamelessly permicious." - Bill Bryson

NK Linked Lecture Series: "Stress, Neurodegeneration and Individual Differences"

I am proud to present an interesting lecture by Dr. Robert Sapolsky, a professor at Standford University and the author of many excellent scientifically themed books aimed towards non-scientists.

Dr. Sapolsky's research interests crosses many fields and disciplines but centers on elucidating how stress mediates its effects on the body from a biochemical perspective.

Wnt Signaling Cascades: Pointing in the Right Direction

A reoccurring theme in signal transduction is for a single spanning trans-membrane receptor to form a homodimer upon signal ligand binding, this step is often crucial for the signal to be transduced into the cell. This applies to numerous hormone receptors, such as the PDGF receptor and the insulin receptor, although the insulin receptor pre-exists as a covalently bound homodimer regardless of an extracellular signal. Based upon a recent publication from Niehrs et al, it appears that the single trans-membrane spanning receptor LRP6 in the Wnt signaling pathway takes this theme up a notch and doesn’t just form a dimer but a large multi-protein oligomer, an in vitro protein aggregate that is an essential for signal transduction in the Wnt pathway. 1
The Wnt signaling proteins, a family of paracrine signaling growth hormones, are crucial to embryogenesis and limb formation in animals and perhaps unsurprisingly has also been implicated in several forms of cancer. Abnormal levels of the Wnt second messenger, Β-catenin, correlate to basal cell carcinoma. The abbreviation Wnt is an aggregation of Wg, as Drosophila Melanogaster flies that had genetic mutations in this pathway were “wingless” and INT, genes found to be involved in vertebrate integration in mice.
At the biomolecular level the Wnt pathway is activated when a Wnt signaling protein binds to two localized receptors; low-density lipoprotein receptor related protein (LRP) and frizzled (FRZ).2 Niehrs specifically analyzed the Wnt3a signaling ligand, which binds to LRP6. After this binding event, LRP6 undergoes phosphorylation by CK1-γ. Once activated, axin binds to the phosphorylated LRP6. For axin to bind to the activated receptor complex it is recruited from a β-catenin degradation complex, that includes axin, GSK-3 and APC; removing axin from this complex results in a loss of this quaternary protein complex’s catalytic power. As a result local Β-catenin concentration increases, permeates into the nucleus and interacts with various TCF/LEF transcription factors, ultimately upregulating gene expression.
Although it was known that Wnt signaling ligands bound to FRZ, it was unclear why it did so as the transduction mechanism appeared to be solely mediated via LRP6 phosphorylation. Why would a cell express two unique receptors, when only one was involved in signal transduction? Furthermore, an additional protein disheveled (Dvl) was implicated in this pathway as a scaffold protein that bound axin and FRZ, but as activated LRP6 also bound axin, the role of Dvl was clearly not well elucidated and seemed somewhat redundant. Additionally, how LRP6 activation occurred by CK1-γ was not clearly defined. With the presence of numerous rogue scaffolding proteins involved in this pathway it was clear that although the overall picture was in focus, the details had still yet to be refined.
Visualizing Wnt signaling by fluorescent labeled Wnt pathway proteins via real-time confocal microscopy, Niehrs found that this pathway involves the formation of ribosome sized aggregates near the cell membrane in Xenopus embryos, HeLa, P19 cells. Niehrs found that these aggregates included: the receptors, LRP6 and frizzled; the sequestered adaptor protein, axin; caveolin, a protein known to be involved in endocytosis and GSK3, an additional protein from the Β-catenin degradation complex and Dvl.
Upon further analysis of these aggregates, Niehrs found that the scaffolding protein Dvl was crucial for the phosphorylation of LRP6. In RNAi knockdown experiments of dvl in MEF cells and the equivalent homolog dsh in Drosophila cells, decreasing dvl levels strongly inhibited phosphorylation of LRP6 through Wnt ligand activation, even though CKI-γ levels were still at a natural level, showing that Dvl is necessary for CK1-γ action. Further experimentation needs to be conducted to determine how Dvl mediates CK1-γ activity towards LRP6; it may act by recruiting CK1-γ to LRP6 or by possibly inducing a conformational change in CK1-γ, inducing activation.
The exciting aspect of this research is the sheer magnitude of the signaling complex. The mass of the signalosome was determined by sucrose density sedimentation via centrifugation, without Wnt3a signaling LRP6 sedimented similarly to a 670 kD protein but upon Wnt3a signaling phosphorylated LRP6 aggregates cosedimented with ribosomal rich fractions. Signal transduction mediated by large-scale protein aggregation is rather unorthodox in the current signal transduction. As a result, our view of signal transduction may need to undergo an expansion.
Most phosphorylated receptors need to undergo endocytosis to remove the phosphate group and return to an inactivated state. Past research by Kikuchi shows that phosphorylated LRP6 undergoes endocytosis by a caveolin-mediated pathway.3 Would this entire complex then undergo endocytosis? It would be interesting to measure the size of these LRP6 endocytosed vesicles, which would allow for an inference of how much of this, as Niehrs states, “LRP6 signalosome” accompanied LRP6. It seems unlikely that the entire aggregate would undergo endocytosis due to the high energy costs associated with forming a lipid bilayer around such a large object. Furthermore, assuming that endocytosis only occurs when the cell wants to terminate the signal, it does not seem plausible that axin would be sequestered, as it would be inhibited from reforming the β-catenin degradation complex.
As this signaling system is crucial to limb formation, it is likely that some sort of gradient or oriented response would be mediated inside the cell. Could the formation of these aggregates, these highly concentrated and localized bundles of activated receptors, be the biomolecular mechanism that governs and orients proper limb formation on an organismal level? Although one can ask numerous questions related to the mechanisms and nature of interactions between these “signalosome” proteins the real issue would be to determine if and how this system creates a gradient of β-catenin into the nucleus and if that then correlates to specific uni-directional cell proliferation.
In highlighting a unique feature in the Wnt signaling pathway, Niehrs discovered a interesting signaling phenomena, which may happen to be the signaling mechanism that mediates oriented limb growth.

References:
1. Wnt Induces LRP6 Signalosomes and Promotes Dishevelled-Dependent LRP6 Phosphorylation. Niehrs et al., Science STKE. June 2007: 1619-1622
2. LDL Receptor-related proteins 5 and 6 in Wnt/B-catenin Signaling: Arrows point the way. Zeng et al. Development. April 2004. 131(8): 1663-77
3. Regulation of Wnt Signaling by Receptor-mediated Endocytosis. Kikuchi et al. J Biochem. April 2007. 141: 443-451

The Histone Code

Lately there’s been a lot of buzz within the scientific community about a “Histone Code”. What is it and why is it important? To understand the importance of this code, we need to set our focus at the origin of this topic. The story starts off with DNA.

The genome, comprised of DNA, is arguably the most important molecule in a cell. Encoded within a DNA molecule are the endless permutations of a repeating code comprised of only four repeating elements, the genome contains the all information needed for that organism to thrive and function; it represents the instruction manual encoding all the instructions on how to build the all the necessary machinery that will be required throughout the organism’s lifetime. The magnitude of this is simply astounding. The situation with DNA is analogous to having every instruction booklet required to build an airplane on one piece of paper, but the paper’s dimensions is that of an extremely long fortune cookie fortune; simply put DNA is a long molecule. Too long, in fact, for a cell to keep it laid straight and still keep it inside the cell. So the cell does the same thing that we do when we have a long piece of rope or unruly string of Christmas lights; the DNA is kept rolled up until it is needed. To accomplish this the cell utilizes a set of proteins, called histones, to start this process of condensing the DNA. In fact the cell uses to so many histones to do this, that it is one of the most prevalent type of proteins in a cell.

Proteins, like DNA, can be thought of as strings (albeit much much smaller) of repeating sequences of different amino acids. These strings of amino acids are almost always folded into different structures. Sometimes proteins are “woven” into sheets, other times into these globular structures as if the string had been tied into a large knot. Interestingly enough, it is that the order of the amino acids themselves that is the main determinant for what kind of shape the protein will form into; this is the case for histones. The sequence of amino acids for a histone causes it to fold into a predictable shape. There are a few different kinds of histones in cells, each with a unique sequence of amino acids and therefore a unique shape. From a cell’s histone arsenal, it utilizes a few different histones to create a multi-protein structure that resembles a neat barrel-like structure that DNA can wrap around; this is referred to as a nucleosome.

Once the DNA is rolled onto these histones, the cell still needs an easy method to lock the DNA away (so it cannot be unrolled) and to release it (so it can read the encoded blueprints); this process is accomplished by histone modification. These modifications are relatively small compared to the overall size of the histone, but they have profound effects.

A cell might modify a histone by adding an acetyl group, a small functional group, to it. In some instances, this modification causes the histone to loosen its grip on the DNA; sometimes it causes a different histone to tighten that grip. Now it might seem a little weird that the same modification causes opposite results. But returning to this “proteins are like strings” analogy, imagine what happens if you take the two ends of a knotted string and pull. What happens? Sometimes the knot gets tighter, other times the knot unravels; the outcome depends on what kind of know it is. A similar situation is occurring with these histones, the result of the modification depends on the structure of the histone.

This is what is the term “histone code” refers to, the attempt to decipher how modifications result in changes in DNA accessibility. Studying the outcome of histone modifications and how they effect the interaction between DNA and histones is currently a hot area of research. The implications of this effect are significant, if a segment of DNA cannot be removed from a histone, the blueprints encoded on the sequence of DNA cannot be read and the cell will miss out crucial pieces of instructions (imagine a plane without a left wing). On the other hand, if a histone cannot hold onto a DNA segment, that segment will be read inappropriately causing to the cell follow the instructions (imagine a plane with extra wings sticking out at odd angles of its body). This is why the histone code is so important; it acts a set of mechanisms that allow the cell the to control when the message from a DNA segment is enacted upon. Histone modifications don’t change the information in a piece of DNA, they just regulate if the message can be read or not.

The NK Linked Lecture Series: The Uniqueness of the Human Brain

An outstanding presentation given by Dr. V.S. Ramachandran. This presentation focuses on neuronal cross-wiring resulting in phenomena such as phantom limbs and synesthesia. This presentation is part of a lecture series by IBM.

A Protein's Manifest Destiny

Do human beings have free will? Or are we subject to some form of manifest destiny, that our calling is pre-ordained? Many people have invested much thought and effort to questions relating to these themes. Due to the nature of such questions and the way that our society works, perhaps there will never be a unified consensual agreement to the answer of these questions.

If we look, an analogous situation is presented in cells. Proteins are subject to diffusion and brownian motion, the molecular equivalent of free will albeit mindless free will. They diffuse haphazardly, randomly; such could be said for an individual's life. A protein could interact with other proteins, aggregating for a while, moving on down a chemical or electrical gradient. But they are not completely free to wander around the cell aimlessly. Within the protein itself exists a manifest destiny, it's signal sequence. Many secretory proteins have an initial sequence that will ultimately be cleaved by a peptidase, but nonetheless this sequence acts as a address on an envelope, labeling the protein. This label determines where it ends up, free floating in the cytosol, packaged into a secretory vesicle, or firmly planted into a membrane.

Maybe the determinants among us can take this as an argument that bolsters their theory but it necessarily isn't. There are exceptions to this rule, many proteins are not labeled with a signal sequence. Once translated they are free to wander about as they please, until they find a suitable partner to interact with or until they age, becoming less functional and eventually inactive.

Free will or determinism. Even a molecular level, we cannot say which is the case.

Science and Engineering Indicators 2006

Find yourself wondering about the state of the science enterprises in the US or abroad? Well, allow your pondering to be inundated with data from the, Science and Engineering Indicators 2006. This report was prepared by the NSF and contains a ridiculous amount of facts, figures and survey results about K-12 science education, labor forces, industry and academic R&D, public attitudes and world-wide S&E economic trends.

A sample of entertaining, interesting and/or depressing data:

"According to one report, "TV weathercasters are often the most visible representatives of science in U.S. households" (NIST 2002)." 1

According to a survey 1/4 of the US population in 2004 did not know that the earth revolved around the sun. 2

"...doctors and scientists received the highest prestige rankings out of 22 occupations. In fact, these were the only occupations seen by more than half of adults (52%) as having very great prestige." 3