The Theory of Everything - String Theory (Part 2)

For many years, the pioneers of string theory struggled with a theory that most physicist just didn't believe in. The basic problem that had most physicists questioning the validity of string theory was that for decades it was believed that the components of the atom could all be classified as point particles, with electrons orbiting around a nucleus of protons and neutrons, which themselves were made up of even smaller 'particles' deemed quarks. In essence, what string theory says is that what we believed to be indivisible point particles were in fact tiny vibrating strings. Furthermore, strings were elegant in their design because of their enormous versatility, for example, just as strings on a musical instrument can vibrate at different frequencies making individual musical notes, in the same way, all the tiny strings of string theory vibrate in different frequencies making up all the fundamental particles and their properties in nature (known as resonance of strings). If we could only understand the properties of these strings, we would be able to explain all the matter and all the forces of nature, from subatomic particles to massive galaxies in our universe. This is the potential of string theory to be the 'theory of everything'.

However, physicists managed to come up with not one, not two, but five string theories! The five theories had many things in common but they had many differences in their mathematics. It was almost embarrassing for string theorist, to say the least, to have five competing string theories that could potentially be the 'theory of everything'.

However, in 1995 at a conference for string theory at the University of Southern California, Edward Witten, an American theoretical physicist with a focus with a focus in mathematical physics, provided a completely new perspective of string theory. He proposed and showed that in fact what we thought were five theories, were just five ways of looking at the same thing. Therefore, all five string theories could be unified into one overall theory, now called M theory, a revolution in string theory, and a possible 'theory of everything'.

However, even M theory had its caveats. Before M theory, string theory consisted of 10 dimensions, with one dimension of time and the 3 dimensions that we are familiar with, plus 6 extra dimensions that are very small and virtually impossible. But M theory demands another spatial dimension, and therefore, there must be 11 dimensions!

Another concept involves the idea that dimensions all have to do with the independent directions in which they can move (called degrees of freedom) and the more dimensions you have, the more you can do. And it became fairly obvious that at the 11th dimension allowed the strings to "stretch" to something like a membrane. A membrane could even be 3 dimensional and with enough energy, a membrane could be as large as a universe! The existence of membranes and extra dimensions reveals a new idea: our whole universe is lying on a membrane inside a much larger higher dimension of space. This raises the possibility that our universe, lying on a membrane, is just a small portion of this larger space, and possibly lies right next to other membranes that contain 'parallel universes'. Some of these universes could be like our own, or it could likely have their own unique laws of nature.

But these parallel universes are not individual compartments in the higher dimensional space, there is one thing that physicists believe that can transverse between universes: gravity. But what makes gravity special? What makes gravity different from anything else in the universe? Following the development of M theory, physicists began to investigate objects other than just strings, one example being membranes. Physicists now believe that matter and energy are actually made up of open-ended vibrating strings with their ends tied down to our 3 dimensional membrane, restricting the matter or energy to our membraned universe. However, closed-looped strings still do exist, and one kind is responsible for gravity (called a graviton). This allows the graviton to travel between the other dimensions and membranes. And if this is the case, then it could be possible to "detect" parallel universes by analyzing these transversing gravitons. And if theoretically there are intelligent lifeforms in these parallel universes, then it could be possible theoretically for this parallel to be very close to us, and thus, theoretically we could "communicate" with these lifeforms using gravity.

This concept of parallel universes could also explain the origins of our very own universe. If we were to turn back time, going further and further back, where our universe was just a very small highly dense point in space we would see that all the laws of physics just break down, and are no longer valid. Not only that, but we also have the problem with the process that initiated the "creation" of our universe, the so-called Big Bang. One of the most imaginative models suggests that the origin of the Big Bang lies in the movement of the parallel universal membranes. According to this proposed model, some time before the Big Bang, two membranes began to drift towards each other until they collided at a specific point, releasing this incredible amount of energy, leading to the Big Bang, and eventually, our universe. What is even more intriguing is that scientists believe that this was not a special event. In fact, it could be absolutely possible that two membranes could've collided prior to the creation of our universe, other membranes could be colliding giving rise to other parallel universes, and this collision will continue to occur in the future. If this idea is true, then it means that somewhere out there is an adjacent membrane on a collision course with our very own universe. However, there is a major problem. The mathematics and laws of nature break down at these early time points, so it is almost impossible to predict what would happen if two membranes were to collide. Would it lead to another Big Bang, or are there other inter-universal possible scenarios?

Of course, these theories seem very amazing and elegant, but they mean nothing if they cannot be proved "in the lab", so to speak. Two of the world's largest particle physics laboratories, fermilab and CERN, are creeping ever closer to answers. The concept here is that hydrogen atoms are electrocuted with huge amounts of electricity, and then they are stripped of their electrons. These energized protons are accelerated through a long underground tunnel system, and just as these protons approach the speed of light, these protons are collided with protons travelling in the opposite direction. Most of the time, the collisions are just glancing blows, but occasionally, there is a direct hit and the result is an explosion of subatomic particles. The hope is that among these subatomic particles is the graviton, which is closed-looped according to string theory, and can travel into the extra dimensions and therefore, the absence of the graviton could be detected.

Another experiment on top of the list for both scientists at fermilab and CERN is the idea of super symmetry, a central prediction of string theory. In essence, super symmetry predicts that for every subatomic particle there exists a paired heavier superpartner (also called a sparticle). If these superpartners exist, they are likely extremely heavy, in fact they may be so heavy that they may not be able to detected with today's "atom smashers" at fermilab and CERN. Although the existence of superpartners won't prove string theory, it will definitely be circumstantial evidence that we are on the right track.

But what if we are unable to find the graviton, or superpartners or even extra dimensions? What if we are unable to find any evidence for string theory? Could string theory be incorrect and is not the road into the 'theory of everything'? The fact of the matter remains, about a century ago some scientists believed they had figured out the laws of the universe, but Albert Einstein came along and revolutionized our views of space, time and gravity. Quantum mechanics revealed a world of unpredictability and bizarre. Regardless of the obstacles, scientific curiosity will keep us going and we will continue to explore the unknown. Undeniably, these new theories of physics shows us the imaginative and creative potential of the human mind.

The Theory of Everything - String Theory (Part 1)

In 1968, a young Italian theoretical physicist named Gabriele Veneziano was searching for equations that would explain the strong nuclear force, which can be defined as the extremely powerful force that binds the neutrons and protons together in the nucleus of atoms. As sometimes the story is told, Gabriele happened upon an old mathematics books where he discovered the Euler beta function, first studied by Leonhard Euler and Adrien-Marie Legendre.

He noticed that when the function was interpreted as a scattering amplitude (In quantum physics, the scattering amplitude is the amplitude of the outgoing spherical wave relative to the incoming plane wave in the stationary-state scattering process), it contained many of the physical properties needed to describe strongly interacting particles.

This amplitude, later named the Veneziano amplitude, is interpreted as the scattering amplitude for four open string tachyons (which will be simply defined here as a hypothetical subatomic particle that moves faster than light).

However, what is more likely is that the discovery of the equations was not accidental but in fact the outcome of intense research and the correlation to string theory was an accidental discovery. But however it was discovered, Veneziano's work led to a model that explained the strong force by a field theory of strings. This was the birth of string theory.

The Euler beta function was passed from colleague to colleague, until it came across the American physicist Leonard Susskind. He understood that this formula explained the strong force mathematically but he figured out that beneath these symbols was something simple, abstract and elegant. The story goes that " a young physicist got stuck in an elevator with Murray Gell-Mann, one of physics' top theoreticians, who asked him what he was working on. Susskind said he was working on a theory that represented particles 'as a kind of elastic string, like a rubber band.' Gell-Mann responded with loud, derisive laughter." He noted that this formula seemed to explain particles with an internal structure, which could stretch and compress and even oscillate. However, as revolutionary as it sounded, it was mainly rejected by the scientific community. It appeared that string theory was dead.

Particle physics was embracing the idea that particles were indeed points and that microscopic particles smashed together at high speeds would lead to release of multiple even smaller particles. But what is revolutionary here is that physicists were not only discovering the constituents of matter, but they realized that the forces of nature could also be described in terms of particles. The way to imagine this is to imagine a game of catch where particles of matter are throwing a particle of force (called a messenger particle) back and forth. The more messenger particles that are exchanged between the particles of matter, the stronger the force, and this is what we feel as force. Experiments by physicists confirmed these predictions by the discovery of messenger particles for electromagnetism, the strong force, and weak force. Using this model, scientists believed that we were once step closer to unifying the forces. To understand this further, imagine we were to rewind time to moments just until after the big bang, when the universe was very much smaller and very much hotter, the messenger particles for electromagnetism and the weak force would have been indistinguishable and would have been united as the ‘electroweak force’. And theoretical physicists believe that if we went further back in time, the electroweak would be united with the strong force. Although that has yet to be proven, quantum mechanics does explain how these three forces operate on the subatomic level. And now we have a consistent model of elementary particle physics that allowed the explanation of all of the interactions – the strong, weak and electromagnetic forces – in the same context known as the ‘standard model’. However, the standard model has a major missing piece. It does not include an explanation for the force that governs the universe, gravity.

Eclipsed by the standard model, string theory started to become very indiscernible by the scientific community. And although, the early pioneers of string theory believed in the model and continued to explore string theory, they found several problems. Among other things, early string theory predicts a particle that can travel faster than the speed of light, an unnatural and hypothetical particle called a tachyon. Furthermore, the theory also predicts 10 dimensions, which at the time was impossible to believe. And to make complications worse, many of the predictions were not testable experimentally classifying this theory as more of a mathematical framework for building models than a physical theory, and to say that string theory is a theory of everything is a failure. Jim Holt, a journalist, was noted as saying “…dozens of string-theory conferences have been held, hundreds of new Ph.D.s have been minted, and thousands of papers have been written. Yet, for all this activity, not a single new testable prediction has been made, not a single theoretical puzzle has been solved. In fact, there is no theory so far—just a set of hunches and calculations suggesting that a theory might exist. And, even if it does, this theory will come in such a bewildering number of versions that it will be of no practical use: a Theory of Nothing.”

By the early 1970s, only a few physicists were still struggling with the concepts and ambiguous equations of string theory. John Henry Schwarz, an American theoretical physicist, was working on some of these inconsistencies, one of them specifically the prediction of a mass-less particle never seen in nature. For several years, he struggled with the equations, but nothing worked, the equations would always seem unruly and messy. Just as Schwarz was thinking about abandoning the theory, he had an idea. What if his equations were describing gravity? That would mean rethinking the size of these ‘strings’ of energy.

By supposing that he was studying the theory of gravity, he had to tremendously change the view of how big these strings were. By suggesting that these strings were actually hundred billion billion times smaller than an atom, the mass-less particle could now be viewed as a ‘graviton’ – the particle believed to transmit gravity at the quantum level – and string theory had described the missing piece of the standard model. Schwarz submitted his results for publication; however, there was very little reaction from physicists. However, Schwarz was not discouraged from his bold predictions. He envisioned that if strings could describe gravity at the quantum level, they must be the key to unifying the four forces – electromagnetic, strong force, weak force, and gravity.

Regardless of this incredible idea, the equations of string theory still contained major mathematical anomalies, and the only way to make string theory viable was to get rid of these anomalies. Schwarz and Michael Green, a British physicist, decided to calculate and it all came down to one equation. The story goes that on one side of the blackboard they got 496. And if they managed to get 496 on the other side, this would prove that string theory was free of anomalies. This was termed the Green-Schwarz anomaly cancellation mechanism and indeed, the two numbers did match and this meant that string theory was free of anomalies and it had the mathematical depth to encompass all fours forces, and the possibility of unification of forces, a dream that Einstein had expressed. This time the reaction of the scientific community was enormous and interest in string theory skyrocketed.

This updated version of string theory seemed capable of explaining all the components of nature. If one imagines the components of an atom: electrons orbiting a nucleus containing neutrons and protons, which are made up of even smaller parts called quarks. String theory explains that the particles making up everything in the universe are made of even unimaginably small strands of energy that look like strings. Furthermore, just as strings of musical instruments have unique vibrational patterns or frequencies that create what we hear as musical notes, the different way that these strings oscillate give particles their unique properties like mass or charge. So in essence, the only difference in particles those make up matter and the particles that make up the forces is the way these tiny strings resonate. And it’s this elegant idea of string theory that one can view the universe as one big musical cosmic symphony.

And it’s this idea that bridges the gap between the unpredictability of the universe on the subatomic level as depicted by quantum mechanics and the smooth picture of the universe on the large scale as depicted by Einstein’s General Theory of Relativity. In essence, string theory ‘spreads out’ the unpredictable nature of a point particle into a string, thereby bringing an ordered fluctuation of quantum mechanics that allows it to stitch together with general relativity.

Regardless of the great advances made so far in string theory, there is still one major criticism, and this leads us back to the Heisenberg uncertainty principle which states that, In quantum mechanics, certain pairs of physical properties, such as position and momentum, cannot be simultaneously known to arbitrarily high precision.

Simply put, the more precisely one property is measured, the less precisely the other can be measured. Therefore, at the distances being studied, experiments cannot be used to validate or refute this theory. And thus, whether string theory can be considered a theory of physics or a theory of philosophy is still highly debated.

Another concept that makes string theory even harder to prove is that one must also consider that this theory predicts extra dimensions of space. Most people consider that the universe has only 3 dimensions and one more dimension of time. We know that Einstein showed that gravity can be visualized simply as warped space-time. Theodor Kaluza, a German mathematician, suggested that electromagnetism might also work the same way. He proposed a hidden dimension where space is warped to facilitate the electromagnetic force. But how can we visualize this extra dimension. Oskar Benjamin Klein, a Swedish theoretical physicist, proposed an unusual answer. Imagine a line that extends between two points, such as a rope tied between two poles. From a distance, we cannot see that the rope has a thickness, and it is simply a line with a single dimension. However, if we were very close to the rope, we would see the presence of a second dimension that wraps around the rope, a dimension that we can travel around the rope in a clockwise (or anti-clockwise) motion. Therefore, dimensions come in two forms, either long like the length of the rope, but can also be very tiny, like the circular direction that wraps around the rope. Kaluza and Klein suggest that the universe may be just like this rope, with both big and extended dimensions, like the ones we know about, but also with small curled up dimensions that are smaller than atoms, dimensions we cannot possible see. Kaluza and Klein theorize that if we were able to decrease our size to the size smaller than an atom, we’d find one extra circular dimension located at every point in space. The concept that extra dimensions exits all around us lies at the heart of string theory, as string theory demands 6 extra dimensions curled up into different shapes at the subatomic level. But how do these extra dimensions of space curled up into unique shapes have any impact on our everyday world? Recall that strings can resonate at specific frequencies, and that this in turn dictates the properties of the particle. When you change the shape of the space around the string, you also change the frequency at which the strings vibrate.

The Earth is Slowing...

The Earth's rotation is the rotation of our planet around its own axis. At present, the angular speed of Earth's rotation in inertial space is 7.2921150 ± 0.0000001 × 10−5 radians per SI second (mean solar second). Multiplying the value in rad/s by Earth's equatorial radius of 6,378,137 m (WGS84 ellipsoid) (factors of 2π radians needed by both cancel) yields an equatorial speed of 465.1 m/s or 1,674.4 km/h.

But is the Earth's rotation slowing down? In short, yes, due to a transfer of Earth's rotational momentum to the Moon's orbital momentum as tidal friction. And with that increase in the Moon's speed, it is also causing the Moon to slowly recede from Earth. The slowing rotation of the Earth results in a longer day and also a longer month. Once the length of a day equals the length of a month, the tidal friction mechanism will stop. But not only is the Earth losing it's kinetic energy to tidal friction, but also other forms of friction.

This on going change causes tremendous dynamic movement within the Earth as it adjusts its shape. It is gradually changing its shape from that of an oblate spheroid with a bulging equator and flatter pole regions to that of a more perfect sphere to conform with the changing conditions. This slow continual change of the Earth's interior has set up tremendous dynamic pressures and stress within the Earth's crust as it endeavors to conform to the ever changing mantle upon which it floats. It is the imbalance between the rotational inertia and gravity that cause the dynamic movements of the continental crustal plates as the crusts shifts and crunches to fit into the ever changing area.It is this constant change thats causes earthquakes to occur, volcanoes to erupt and the Earth's vast mountain ranges to rise. As the equatorial oblate shape of the Earth shrinks, the immense resulting pressure within the mantle causes it to gradually ooze upward creating the Atlantic and Pacific ridges.

Does this spell a slow but inevitable doom for our planet, or are there more imminent threats to our survival? In any case, we are on this Earth but only just a moment, and will be gone just as quick.


Arthur N. Cox, ed., Allen's Astrophysical Quantities p.244.

Hey you guys work with stem cells, right?

Here is a question I received from a friend asking about the differences between embryonic stem cells and induced pluripotent stem cells:

Questions: A friend of mine posted an article saying that embryonic stem cell research is useless because it can all be done with induced pluripotent stem cells. That seems incorrect to me. Could you give me some insight into this issue?

My Answer: Sure, you're right. Embryonic stem cells are NOT the same as induced pluripotent stem cells. This is a common statement that people (usually idiots who read newspaper headlines and don't bother to actually read the research). Also the reason for this could also be because the term "stem cell" is such a buzz word now and almost everything is called a stem cell. Lets review a few of the criteria for a "stem cell".

1. Immortality
Incorrect, stem cells are NOT immortal. They can generate many progenitor cells over their lifetime by assymetrical cell division, but they are by no means immortal.

2. Can form multiple cell types. This has really only been shown in vitro. So a "stem cell" is put into a media and then forms different cells. Not really been conclusively shown in vivo, and if it was conclusive in vivo, we'd have cured spinal cord injuries by now. Fact of the matter is, the way cells behave in vitro is not the same as how cells behave in vivo.

Also, certain "stem cells" only produce 1 type of cell. A muscle satellite cell is a stem cell, but it only produces only 1 cell type (muscle cells). But it is present in senescence and has the potential for many cell divisions.

3. Stem cells are special and other cells cannot normally become stem cells. There is evidence that liver cells can undergo a dedifferntiation following injury/loss of regions of the liver.

In terms of ES vs. iPS cells:

ES and iPS cells are similar yes, but NOT THE SAME. ES cells come from 5-6 day old embryos after in vitro fertilization. These cells can turn into all cells of the body. iPS cells come from adult cells that are reprogrammed to "act" like embryonic stem cells. I believe you can activate 4 specific genes that can "reprogram" an adult cell to an iPS cell. They can also form all cells of the body.

But the issues arise when we look at the methods of creating iPS cells. The methods vary between labs, the cells produced by different labs behavior differently, and simply, comparing ES and iPS cells on a genetic level shows that DIFFERENT GENES ARE ACTIVATE between ES and iPS cells. For example recently, European and Israeli researchers found that when they created iPS and ES cells both containing a mutation that causes fragile X syndrome, the two groups of cells behaved very differently, with the iPS cells not even activating the mutated gene (FMR1). It is possible (if not very likely) that other genes may likewise escape the reprogramming process leading to iPS cells.

The Immune System in Health and Disease: Volume I

Introduction to Immunology

It is said that the field of immunology began with Edward Jenner who discovered in 1796 that cowpox could be used to induce protection against human smallpox. Jenner called this procedure vaccination, and this term is still used to describe individuals who have been injected with weakened or attenuated strains of disease-causing agents to confer protection from (often) fatal diseases. Almost two centuries later, from the initial pioneering work of Jenner, the smallpox vaccine was universal and in 1979, the World Health Organization declared smallpox eradicated.

In the late 19^th century, Robert Koch proved that infectious diseases are caused by microorganisms, with each one responsible for a particular disease. In fact, Koch defined what is now known as Koch's Postulates (which every basic course on immunology loves to test).

1. The microorganism suspected of causing pathology must be found in abundance in all organisms suffering from the disease, but should not be found in healthy animals.

2. The microorganism must be isolated from a diseased organism and grown in pure culture.

3. The cultured microorganism should cause disease when introduced into a healthy organism.

4. The microorganism must be reisolated from the inoculated, diseased organism and identified as being identical to the original specific causative agent.

Currently, disease-causing organisms or pathogens, can be grouped into four broad categories: viruses,bacteria, pathogenic fungi and parasites.A proteinaceous infectious particle, or prion, is an infectious agent composed primarily of misfolded protein and is sometimes considered as another category of pathogen.

Further advancements came in the 1800s, Louis Pasteur developed a vaccine against cholera in chickens, and also developed a rabies vaccine. Emil von Behring and Shiasaburo Kitasato discovered that serum from animals that were immune to diphtheria or tetanus contained an "antitoxic activity" that could confer short-term immunity to unimmunized animals. This "antitoxic activity" would later be termed antibodies.

Components of the Immune System

The immune response can be broadly classified into the innate and adaptive immune responses. The innate immune system comprises the cells and mechanisms that defend the host from infection in a non-specific manner. The innate immune system responds rapidly against infectious agents but unlike the adaptive immune system, it does not confer long-lasting or protective immunity to the host. The innate system is thought to constitute an evolutionarily older defense system, and is the dominant immune system found in plants, fungi, insects, and in primitive multicellular organisms. Elie Metchnikoff discovered that many microorganisms could be engulfed and digested by specialized phagocytic cells. These cells, now called macrophages, are a key component of the innate immune system and will be studies in more detail later. The major functions of the vertebrate innate immune system include:

1. Recruiting immune cells to sites of infection, through the production of chemical factors, including cytokines andchemokines.

2. Activation of the complement cascade to identify bacteria, activate cells and to promote clearance of dead cells or antibody complexes.

3. The identification and removal of foreign substances present in organs, tissues, blood and lymph, by specialized white blood cells.

4. Activation of the adaptive immune system through antigen presentation.

The adaptive immune system is composed of highly specialized, systemic cells and processes that eliminate or prevent pathogenic challenges. It provides specific immune responses, such as the production of antibodies against particular pathogens and it can retainimmunological memory because it confers immunity against the same pathogen during the lifetime of the individual. The adaptive immune system is highly adaptable because of somatic hypermutation (a process of accelerated somatic mutations), and V(D)J recombination (an irreversible genetic recombination of antigen receptor gene segments). These mechanisms allow a small number of genes to generate a vast number of different antigen receptors, which are then uniquely expressed on each individual lymphocyte, and confer the ability to recognize millions of pathogenic organisms and mount a specific response to each.

Matrix Metalloproteinases in Central Nervous System Disease

CNS injury triggers a host immune response that generates inflammatory cytokines that increase BBB permeability and mediates the recruitment of peripheral immune cells. matrix metalloproteinases (MMPs) have been implicated in many CNS diseases (Kieseier, Seifert et al. 1999; Hashimoto, Wen et al. 2003). During injury, resident CNS cells and peripheral infiltrating leukocytes can secrete cytokines and MMPs which mediate inflammation by the acute opening of the BBB, demyelination and axonal injury, and cell death (Rosenberg 1995; Kieseier, Seifert et al. 1999; Yong, Power et al. 2001). MMPs and tissue inhibitor of matrix metalloproteinases (TIMPs) have been implicated in MS and EAE and MMP genetic polymorphisms are associated with risk and clinical course of MS (Dasilva and Yong 2008; Mirowska-Guzel, Gromadzka et al. 2009; Alexander, Harris et al. 2010). MMP-12-null mice induced with MOG_35-55 peptide EAE exhibit a more severe disease course than wildtype controls (Weaver, Goncalves da Silva et al. 2005). During EAE disease onset and prior to clinical symptoms, MMP-12 is highly expressed and secreted by a subpopulation of monocytoid Iba-1-reactive cells, resident microglia and infiltrating macrophages (Dasilva and Yong 2008). MMP-12 expression and activity continues into the early phase but is lost following peak clinical disease (Dasilva and Yong 2008).

During early CNS disease, astrocytes become reactive and respond in astrogliosis, and mediate many pathogenic mechanisms. It has been shown that astrocytes increase MMP-13 expression in a time-dependant manner in various diseases (Brinckerhoff, Rutter et al. 2000; Stickens, Behonick et al. 2004; Lu, Yu et al. 2009). Furthermore, astrocyte-derived MMP-13 perturbs the continuity and mediates the destruction of the ZO-1 protein which leads to increased BBB permeability in hypoxic brain injury (Lu, Yu et al. 2009). In addition to MMP-13, reactive astrocytes also increase their expression of MMP-9 in various CNS injury models (Bauer, Burgers et al. 2010; Wang, Hsieh et al. 2010) It has been shown that MMP-9 mediates increased BBB permeability via gap formation and tight junction protein (occludin and ZO-1) discontinuity (Bauer, Burgers et al. 2010). Treatment with an MMP inhibitor reduced vascular leakage and attenuated TJ disorganization (Bauer, Burgers et al. 2010). BBB hyperpermeability allows CNS infiltration of leukocytes which secrete a variety of cytokines and factors, among them is leukocyte-derived MMP-9, which exerts its proinflammatory actions by promoting leukocyte recruitment and migration in CNS parenchyma (Gidday, Gasche et al. 2005; Zozulya, Reinke et al. 2007).

Inflammatory cytokines and signaling factors play an important role in the regulation and activity of MMPs. Tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1 β), two key factors implicated in MS and EAE, are closely associated with the disruption of the BBB (Sharief and Thompson 1992) and TNF-α, IL-1β, and platelet activating factor (PAF) are implicated in MMP production, specifically MMP-9, 12 and 13 (Birkedal-Hansen, Moore et al. 1993; Lee, Shin et al. 2003). Transforming growth factor (TGF)-ß mediates increased in vitro endothelial cell layer permeability by inducing MMP-9 expression which leads to reduced occludin levels in TJs (Behzadian, Wang et al. 2001). In many CNS injury models including EAE, BBB hyperpermeability is dependent on vascular endothelial growth factor (VEGF) which mediates changes in TJ protein expression and rearrangement (Proescholdt, Jacobson et al. 2002; Schoch, Fischer et al. 2002; Sasaki, Lankford et al. 2010). VEGF increases endothelial permeability through direct activation of MMP-9 and inhibition of VEGF not only blocks vascular leakage but also attenuates MMP-9 activity (Bauer, Burgers et al. 2010).

Alexander, J. S., M. K. Harris, et al. (2010). "Alterations in serum MMP-8, MMP-9, IL-12p40 and IL-23 in multiple sclerosis patients treated with interferon-beta1b." Mult Scler 16(7): 801-9.

Bauer, A. T., H. F. Burgers, et al. (2010). "Matrix metalloproteinase-9 mediates hypoxia-induced vascular leakage in the brain via tight junction rearrangement." J Cereb Blood Flow Metab 30(4): 837-48.

Behzadian, M. A., X. L. Wang, et al. (2001). "TGF-beta increases retinal endothelial cell permeability by increasing MMP-9: possible role of glial cells in endothelial barrier function." Invest Ophthalmol Vis Sci 42(3): 853-9.

Birkedal-Hansen, H., W. G. Moore, et al. (1993). "Matrix metalloproteinases: a review." Crit Rev Oral Biol Med 4(2): 197-250.

Brinckerhoff, C. E., J. L. Rutter, et al. (2000). "Interstitial collagenases as markers of tumor progression." Clin Cancer Res 6(12): 4823-30.

Dasilva, A. G. and V. W. Yong (2008). "Expression and regulation of matrix metalloproteinase-12 in experimental autoimmune encephalomyelitis and by bone marrow derived macrophages in vitro." J Neuroimmunol 199(1-2): 24-34.

Gidday, J. M., Y. G. Gasche, et al. (2005). "Leukocyte-derived matrix metalloproteinase-9 mediates blood-brain barrier breakdown and is proinflammatory after transient focal cerebral ischemia." Am J Physiol Heart Circ Physiol 289(2): H558-68.

Hashimoto, T., G. Wen, et al. (2003). "Abnormal expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in brain arteriovenous malformations." Stroke 34(4): 925-31.

Kieseier, B. C., T. Seifert, et al. (1999). "Matrix metalloproteinases in inflammatory demyelination: targets for treatment." Neurology 53(1): 20-5.

Lee, W. J., C. Y. Shin, et al. (2003). "Induction of matrix metalloproteinase-9 (MMP-9) in lipopolysaccharide-stimulated primary astrocytes is mediated by extracellular signal-regulated protein kinase 1/2 (Erk1/2)." Glia 41(1): 15-24.

Lu, D. Y., W. H. Yu, et al. (2009). "Hypoxia-induced matrix metalloproteinase-13 expression in astrocytes enhances permeability of brain endothelial cells." J Cell Physiol 220(1): 163-73.

Mirowska-Guzel, D., G. Gromadzka, et al. (2009). "Association of MMP1, MMP3, MMP9, and MMP12 polymorphisms with risk and clinical course of multiple sclerosis in a Polish population." J Neuroimmunol 214(1-2): 113-7.

Proescholdt, M. A., S. Jacobson, et al. (2002). "Vascular endothelial growth factor is expressed in multiple sclerosis plaques and can induce inflammatory lesions in experimental allergic encephalomyelitis rats." J Neuropathol Exp Neurol 61(10): 914-25.

Rosenberg, G. A. (1995). "Matrix metalloproteinases in brain injury." J Neurotrauma 12(5): 833-42.

Sasaki, M., K. L. Lankford, et al. (2010). "Focal experimental autoimmune encephalomyelitis in the lewis rat induced by immunization with myelin oligodendrocyte glycoprotein and intraspinal injection of vascular endothelial growth factor." Glia.

Schoch, H. J., S. Fischer, et al. (2002). "Hypoxia-induced vascular endothelial growth factor expression causes vascular leakage in the brain." Brain 125(Pt 11): 2549-57.

Sharief, M. K. and E. J. Thompson (1992). "In vivo relationship of tumor necrosis factor-alpha to blood-brain barrier damage in patients with active multiple sclerosis." J Neuroimmunol 38(1-2): 27-33.

Stickens, D., D. J. Behonick, et al. (2004). "Altered endochondral bone development in matrix metalloproteinase 13-deficient mice." Development 131(23): 5883-95.

Wang, H. H., H. L. Hsieh, et al. (2010). "Endothelin-1 enhances cell migration via matrix metalloproteinase-9 up-regulation in brain astrocytes." J Neurochem 113(5): 1133-49.

Weaver, A., A. Goncalves da Silva, et al. (2005). "An elevated matrix metalloproteinase (MMP) in an animal model of multiple sclerosis is protective by affecting Th1/Th2 polarization." FASEB J 19(12): 1668-70.

Yong, V. W., C. Power, et al. (2001). "Metalloproteinases in biology and pathology of the nervous system." Nat Rev Neurosci 2(7): 502-11.

Zozulya, A. L., E. Reinke, et al. (2007). "Dendritic cell transmigration through brain microvessel endothelium is regulated by MIP-1alpha chemokine and matrix metalloproteinases." J Immunol 178(1): 520-9.

New Research into Ischemic Stroke Treatment

A stroke (also called a cerebrovascular accident or CVA) occurs due to reduced blood supply to the brain that results in loss of brain functions. This reduction can be due to ischemia caused by a thrombosis or embolism or due to a hemorrhage,which is the leakage of blood into tissues; hence the terms ischemic and hemorraghic stroke. Ischemic strokes are treated with thrombolysis which serves to dissolve the clot. The current preferred treatment for ischemic strokes is a drug called rtPA (recombinant tissue plasminogen activator). As with most stroke drugs, rtPA must be administered within the first few hours of a stroke or the risks of treatment outweigh the benefits. A potential risk involves a sudden rise in blood pressure due to the dissolving of the clot, which can subsequently lead to blood vessel rupture and bleeding into the brain.

Less than 10% of stroke victims will make it to the hospital early enough to be treated with rtPA. The rest are given drugs that reduce the possibility of futher clot formation but do not dissolve the initial clot. A reason for this includes the diagnosis of the type of stroke by brain scans. Administration of rtPA, or other "clot busters", in hemorrhagic stroke will lead to increased bleeding into the brain.

New research shows that tPA (tissue plasminogen activator) can be released by neurons themselves. In a postulated hypothesis, tPA in small quantities can bind to NMDA receptors. Normally, NMDA receptors allow the influx of sodium and calcium, the latter mechanism being important for learning and memory. But damaged neurons, for example, during stroke, release tPA in large quantities. High levels of tPA can cause neighboring neurons to die, by NMDA-mediated excitotoxicity, and can even damage the blood-brain barrier.

Mechanistically, it is possible to prevent the association of tPA with NMDA receptors by antibody neutralization. In mouse stroke model studies, injection of anti-tPA antibodies resulted in reduced stroke-inflicted brain damage both on its own or in combination with administered rtPA both following stroke and 6 hours later. Using the antibody, not only did the researchers see a decreased level of brain damage but also the antibody seems to work beyond the current critical time window.

Newscientist article: http://www.newscientist.com/article/mg20727682.500-antibody-cuts-brain-damage-in-strokes.html