caudoviral

Discussions and reflections on science and life

HIV & HSC

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They haven’t managed to kill me with exams yet; however, it’s not from lack of trying. But I found something so interesting yesterday that I just couldn’t keep myself from blogging about it. And by interesting, I mean terrifying. I tend to find life beautiful. Even if it is something most people would find gross, or disturbing, or horrible. I’m a biologist, it’s a documented weakness of our ilk. So when I say that the following engenders in me a feeling of profound wrongness and almost disgust, I want you to take my full meaning.

First, background:

  • HIV comes in two flavors, CCR5 tropic and CXCR4 tropic. You might remember a post on CCR5 tropic HIV from a while back. It basically denotes which co-receptor is necessary for the virus to enter a cell (and yes, there are dual-tropic strains). We generally focus on CCR5 because, for reasons that are not entirely clear, initial infection with HIV is almost entirely CCR5 tropic with the infection shifting to CXCR4 tropic as it progresses.
  • Hematopoietic stem cells (HSC) are the source of all of your blood. ALL of your blood, myeloid and lymphoid. They are a self-renewing pool of multipotent cells, which means that they can be used to make new blood as needed (this is why you can donate blood and bone marrow have it regenerate). Among the offspring of the lymphoid lineage are the T-cells that HIV usually attacks.

Got all that? Good. Sit down. Are you sitting comfortably?

In sum, we have shown that multipotent HSPCs and HSCs can be infected by HIV and that this infection is primarily accomplished by CXCR4-tropic HIVs. The infection and destruction of multipotent HSPCs may contribute to the more rapid decline in CD4 counts associated with CXCR4-tropic HIV isolate emergence. Alternatively, as infected HSCs could create an extremely long-lived reservoir of virus, preferential infection of these cells by CXCR4-tropic virus could provide a reservoir for the emergence of CXCR4-tropic isolates late in disease: as other viral reservoirs are depleted, CXCR4-tropic virus from the HSC and HSPC reservoir could begin to predominate. In addition, our demonstration that HIV can infect cells capable of stably engrafting for months in the xenograft model indicates that HIV can infect HSCs that are capable of self-renewal and, if the integrated viral genome is latent, that it can be maintained and even expanded by cell division.

The above quote comes from an article published in this month’s Cell: Host & Microbe, and I have to say that their work looks pretty solid (at least to my exam addled brain). They performed a series of experiments using viruses generated from a minimal HIV genome and expressing three variant (R5, R4, or dual) envelope proteins. With this they demonstrated that not only could CXCR4 tropic and dual tropic viruses infect hematopoeitic progenitor cells in general, but that they could specifically do so to cells capable of multilineage reconstitution in immunocomrpmised mice. Or to put it another way: XR4 and dual tropic HIV infects HSC.

Now active HIV infection appears to kill HSC cells outright, and HSC death is really bad, but if you have been following closely you’ll realize that that isn’t the biggest worry here. Latent infection of HSC could lead to a near impossible to purge, continually renewing reservoir of infection, moreover it appears that it is possible for infected HSC to differentiate and produce daughter cells that are already infected. This means that in advanced cases of HIV infection, we might need to start looking for integrated provirus in cells that HIV technically can’t infect.

This is a blow struck to the heart of our immune system. Sure, there are genetic disorders that screw with HSC, cancers even, but a pathogen? I feel like they are breaking the rule about fighting on holy ground. It is still important to see if wild-type HIV is capable of latently infecting HSC instead of killing them outright, but given the versatility of this virus, it wouldn’t surprise me, and if that is the case it is all the more reason to lock down HIV infection as early as possible. We are really close to finding a way to flush latent infection from T-cells, and it would be a serious blow if we succeed in that only to find that HIV has yet another reservoir lying in wait.

(And okay, I admit that my disgust is laced with a teensy bit of: Oh wow that is so awesome.)

Notes & Sources

  1. HIV-1 Utilizes the CXCR4 Chemokine Receptor to Infect Multipotent Hematopoietic Stem and Progenitor Cells (Carter, et al. 2011)
  2. Thats only the second Highlander joke in three months of science blogging. I am falling behind schedule.
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Written by Caudoviral

03/25/2011 at 14:13

Posted in Biology, HIV/AIDS

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Facts on Acute Radiation Syndrome (ARS)

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Now that we have a basic idea of what ionizing radiation is, let’s talk about what it does to you. Today we will focus on acute radiation syndrome (also known as radiation sickness and radiation poisoning). This is the sort of thing that occurs due to short-term, high-dose exposure to ionizing radiation, such as that from nuclear weapon discharge or nuclear industrial accidents. We’ll take a look at the long term effects and generation of neoplasms in a future post.

The precise nature of radiation syndrome varies by dose, radiation type, tissue exposed, and duration of exposure. These factors are all rolled together in an SI unit called the Sievert (Sv), which is known as the dose equivalent. The measure of dose is known as the Gray (Gy), but that raw information doesn’t tell us much about biological effect. So the Gray is transformed as a function of quality factor Q which is the ratio between the effects of gamma radiation and the effects of your radiation type of interest (e.g. Q[gamma]=1, Q[alpha]=20). There is a further factor called N which relates the effects of radiation based on differences in species and tissue, for simplicity’s sake N[human]=1. The final product of this calculation is the dose equivalents in Sv, which gives us useful info on biological effect. The units of Gy and Sv are J/kg and because time is an important factor we usually see Gy and Sv expressed over seconds, hours, or days. Both the Gy and Sy deal with pretty large amounts of radiation, so it is much more likely to see quantities expressed in milli or micro versions (for instance at one point the ongoing Fukushima I accident peaked at 400 mSv/hour).

Certain types of (particle based) ionizing radiation are of greater or less concern depending on the location of their source. For instance, alpha and beta-particles have low penetrance. They can cause surface skin burns, but generally can’t penetrate far enough to cause excessive internal damage. However, an internal source of alpha or beta-particles is a more dire circumstance because just as they do not have the penetrance to enter the body, they cannot leave. This is why contamination of food, water, and dust is such a concern. High penetrance radiation, like neutron radiation or (photon based) gamma-rays is less affected by location of source.

The symptoms of radiation syndrome begin at 1 Sv and at about 8 Sv they become invariably fatal. Not all symptoms present at once, and it can take up to four weeks for the full effects of minor radiation poisoning to be seen. Usually the time between exposure and onset decreases as the Sv increase (with there being very little delay at the  8 Sv level). The immediate symptoms include: nausea and vomiting, diarrhea, headache, and fever. These occur within ten minutes to six hours after exposure. In the next one to four weeks (or sooner in the case of extremely high doses) the victim may suffer: fatigue, hair loss, bloody vomit and stools, infections, poor wound healing, low blood pressure, dizziness, and disorientation. Usually there is also some level of skin redness, peeling, ulceration, and possibly necrosis.

All of these symptoms result from a disturbance in cellular chemistry. As we discussed last time, ionizing radiation generates ions (particularly reactive ions known as free radicals). The cell is an impressive machine dedicated to controlling multiple ongoing, complex chemical reactions. So we can see why the spontaneous introduction of new reactants would be bad, and why a high concentration of them at one time would be very bad. Essentially cells will be faced with a critical failure of their functions and this will lead to massive cell death. And this is not going to be the pretty, well-controlled cell death either (no, that isn’t facetious, remind me to tell you about the pathways of cell death sometime). In most cases the immediate cause of death is opportunistic infection due to a failure of the immune system caused by the destruction of large amounts of bone marrow; however, in extreme cases the victim just basically falls apart at a cellular level.

As mentioned, these are only the acute affects of radiation exposure, even if you survive these, there are still the long-term consequences of cell damage to look forward to.

This is what is at stake in Japan. This is what a whole host of brave rescue workers are risking to try to keep everyone else safe. Show a little compassion and (if you can) a little support.

Sources & Further Reading

Written by Caudoviral

03/18/2011 at 16:48

Posted in Biology, Chemistry, Health, Physics

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A quick primer on ionizing radiation

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With an eye towards discussing the effects of ionizing radiation on humans, particularly with respect to cancer, I thought it would be best to write up a quick and dirty reference post on what exactly ionizing radiation is. This is a good example of my continuing struggle to find an appropriate voice for this blog. I never really know what I can safely assume my readers know. So, let’s (hopefully) review:

Ionizing radiation consists of particles or photons capable of inducing detachment of electrons from their atoms resulting in free electrons and a corresponding positive ion. There are five broad types of ionizing radiation: alpha-particles, beta-particles, neutron radiation, gamma rays, and X-rays.

  • alpha-particles: result from radioactive decay, and consist of two protons and two neutrons. They are directly ionizing.
  • beta-particles: result from radioactive decay, and consist of either an electron or positron. They are directly ionizing.
  • neutron radiation: results from nuclear fission, and is simply a free neutron. They are indirectly ionizing as they have no charge themselves, but can collide with and excite charged particles that then directly ionize.
  • gamma rays: are high frequency photons emitted to right the energy of a decayed atomic nucleus. They are also indirectly ionizing as they are chargeless wave-packets that when absorbed can cause electron expulsion which then ionizes directly.
  • X-rays: kind of overlap with gamma rays. They are high frequency photons. The only major difference is their origin.

The ionizing capability is dependent on the energy of the individual unit (particle or photon) interacting with the atom (this is why high frequency electromagnetic waves are ionizing and low frequency are not). Thus, high energy, low concentration radiation can still have an ionizing effect.

As we will discuss next time, it is generally the chemical characteristics of the resulting ions that cause damage in cell physiology and DNA.

Written by Caudoviral

03/16/2011 at 23:07

Posted in Physics

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It’s all fun and games ’till…

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Okay, so I had a friend ask me to talk a little bit about the basics of nuclear radiation and its effect on humans. This question specifically prompted by the tragedy that has recently occurred in Japan. And I intend to do that throughout the rest of the week, but today was…taxing (and technically it is Tuesday here now).

I just want to make a brief note about something else that has happened recently. A massive outpouring of (predominantly American) online vitriol against Japan. Ignorant and Online is doing a good job cataloging the more egregious of these. This ranges from insensitive jokes to rage filled tirades, and seems to be motivated by everything from old grudges to crazy religious theories. I had an acquaintance trying to send me his own crude jokes not two hours ago. He seemed unabashed when I politely explained that he wasn’t being witty and called me a person who prefers to cry at tragedy rather than laugh at it. I wish I did cry more, it would probably be healthier.

I can see the value in pain based physical comedy, I enjoy dark humor, and I don’t shirk away from death in my entertainment media. But to be perfectly clear: when real people begin to suffer and die, things stop being entertaining. When confronted with a tragedy, the appropriate response is to do something about it, and leave people who are more concerned with laughing or crying on the sidelines because you don’t need them getting in your way. Human suffering is not a spectator sport.

There are earthquake victims, tsunami victims, radiation victims, and a host of people without water, power, or food. Dedicated members of Japan’s SDF and international aid organizations are risking their lives to do something about it. As I write this, a skeleton force of fifty people have taken it upon themselves to wage an uncertain war pumping sea water into a nuclear complex to try and prevent more explosions, more radiation, more sickness, and more death.

This is not funny. Making a litany of (predominantly racist) jokes about this is not a way of “whistling in the dark” or a “valid method of dealing with tragedy”. Either do whatever you can to help these people (which may validly be very little, I personally can’t do much more than donate to aid organizations) and show a little bit of decorum and decency. The last thing you should do is laugh at their suffering and the work of those trying to help.

Thank you.

Written by Caudoviral

03/15/2011 at 00:25

Posted in Personal

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Review: Daphne in the Brilliant Blue

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It’s Friday, and Spring Break, so time to focus on something a little less mentally taxing. Namely: anime. Now, with age and taste comes a little less of the geeky obsession I had with it in my highschool and undergraduate years, but certain, select titles still make up a solid twenty percent or so of our DVD collection. Why? Because it is a great vehicle for speculative fiction. By using an animated medium you dodge the cost spikes of practical and computer generated effects and it becomes no more difficult to make breathtaking and bizarre scenes than it does to make mundane ones. You can take an interesting premise or setting and explore it in a manner unconstrained by skyrocketing budgets.

This is exactly what Daphne in the Brilliant Blue fails to do.

Abstract

Animated by J.C. Staff and produced by Genco, Daphne in the Brilliant Blue is a sci-fi/action story set in a flooded world. Humanity survived the deluge by building underwater cities where they preserved themselves and a great deal of Earth’s animal life. At an appointed time, 100 years before the start of the series, all (but one) of the submerged cities rise to the surface to form floating city states associated with whatever remaining land masses they can find. Society is rebuilt under the watchful gaze of a centralized government, scientific, law-enforcement organization known as the Ocean Agency.

The story opens with our young heroine, Maia Mizuki, completing her application for employment with said agency. Despite receiving top marks she is denied a position with the Ocean Agency, and not having made any alternate plans, winds up frantically looking for work. After a few traumatic incidents and with a bit of luck she finds a job with a rough and tumble company of freelance problem solvers called Nereids. Over the next year with Nereids, Maia grows up and begins to unravel her (apparently requisite in these sorts of series) mysterious past.

Discussion

I love this premise and setting. Further, it is animated by a great studio. About a week ago, when I saw that this was up on Hulu and realized that my weekend was mostly free, I wound up sitting down to watch it with high hopes. Those hopes were quickly dashed.

The beginning of the first episode seems almost promising. We open on a young girl salvaging a box from a wrecked ship, some friendly ocean life, and a submersible hover bike/jetski. But right after that things begin to go…well, not really bad, but weird. From the second episode on I felt like I had stumbled into a different show: some kind of all-female scantily clad Cowboy Bebop/Firefly knockoff with a bit too much absurdist comedy tossed in for good measure. And things never really circled back until the last one or two episodes of the twenty-four episode series. But by that time I had mostly lost interest and none of the reveals that they were poorly building to seemed that important or surprising (save for the one about the true nature of Maia’s grandfather, that was kind of neat).

I don’t think I have ever been so let down by a show. I was really hoping for at least some sense of curiosity or wonder about this cool world with its strange cities and tech. Where does their food come from? How do the mouthpieces that let the characters breath under water work? What terrestrial life has been preserved and what hasn’t? How do they obtain fresh water? How were these cities constructed? How the hell do those bathing suits even stay on…spirit gum? There is quite a bit to explore here and the setup is so interesting, yet the creators seem to think that the only thing their audience should be interested in is guns and T & A. Which is profoundly disappointing.

This is not a bad show. It’s certainly well animated and I am sure that a number of people will be able to find it passably entertaining. There are even obscene amounts of exploitative fanservice (I will grant that the whole aquatic world  concept well justifies putting their characters in swimsuits…but nothing justifies the specific swimsuits they decide to use) for those who are into that. But it is certainly not a good show and really fails to live up to the promise of its setting. I suppose if I want my aquatic cyberpunk fix I will just have to go read Starfish again.

Written by Caudoviral

03/11/2011 at 14:40

Posted in Review, Spec-Fic

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Dang are they weird…but what would we do without them?

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So, Val asked in the comments:

As someone with a sweet tooth for speculative biology, I can’t help inquiring as to the materials which you refer in this passage:
“although there have been some theories about alternate high yield ATP production pathways or schemata of power management”

Could you please point me towards sources where I can find out more about said hypothetical pathways and power management schemata?

And since it is an interesting question, and since I should be making a post today anyway, and since I made a mistake in that initial statement that needs to be fixed, I thought I would go ahead and take a shot at answering it out here on the frontpage.

Firstly, I need to admit that I mistyped that first part and clarify a bit. I am not personally aware of any proposed higher yield pathways (although I would not be surprised if they were out there, but that level of biochem is a region to which I venture only rarely). When we talk about the yield of a metabolic pathway we generally express it in terms of the amount of product per cycle or the amount of product per amount of reactant. What I meant to say was that there are theories concerning how to increase the amount of product per time. The distinction may seem academic, but a faster pathway generating less ATP per cycle is technically lower yield than a slow pathway generating more ATP per cycle, even if the faster one produces more net ATP in the same amount of time. So what I meant to say was that there were “theories about alternate high rate ATP production pathways“. I hope that clears things up.

For those of you who don’t know, our (and other aerobic metabolizers) primary method of ATP production is a process called oxidative phosphorylation, which is dependent on our mitochondria. It is a low rate, high yield process resulting in ~32 mol ATP per 1 mol glucose. The primary method of ATP production in anaerobes is fermentation. It is a high rate, low yield process resulting in 2 mol ATP per 1 mol glucose. This trade off between yield and rate seems to be a necessary physical constant due to thermodynamic principles. All eukaryotic, multicellular life is dependent on aerobic metabolism. It’s just good evolutionary sense, as detailed in “Cooperation and Competition in the Evolution of ATP Producing Pathways” (Pfieffer, et al. 2001). But does it have to be? The answer is: probably not.

In fact, depending on what your definition of eukaryotic, multi-cellular life, then the answer is a firm “no”. Most cancers do not make use of oxidative phosphorylation even in an aerobic environment. This phenomenon, known as the Warburg effect, hinges on two factors: (1) as Pfieffer, et al. show, high rate low yield ATP producing pathways are selected for in cases of competition for resources (and the cancer can be seen as an independently evolving, parasitic entity in competition with its host); and (2) the intermediates generated by glucose metabolism are requisites for growth, thus proliferating eukaryotic cells benefit more from a higher concentration of glycolytic intermediates than they do from a higher concentration of ATP. A good review of the history and current research on the Warburg effect is “Cancer metabolism: the Warburg effect today” (Ferreira 2010).

If we take the Warburg effect as a real-life, proof of concept, the speculation can extend down to main paths: (1) eukaryotic cells do not possess a pressure for high yields of ATP under all conditions; and/or (2) a sufficiently high rate in the appropriate environment could overcome the pressure towards high yields.

Towards the first point we can imagine a form of eukaryotic life that goes through metamorphic phases, for instance a proliferative phase that requires high metabolic intermediates and low ATP before metamorphosing to an active phase at which point ‘banked’ ATP could be used in one great sprint to breed and die. Something very similar occurs in the male fish of the family Cetomimidae which take up energy in a larval phase and expend it in a brief mature phase (Johnson, et al. 2009). Of course in our putative life form the immature phase would be in complete torpor, again something we see in the metabolism of certain existent creatures like hummingbirds that go through cycles of torpor and energy expenditure. An exploration of this concept can be found in the speculative fiction novel Blindsight, by Peter Watts.

The second path is a bit more open. Quantum tunneling has been shown to increase the rate of biochemical reactions by over 100 fold, as yet unknown enzymatic activity could boost reaction rate through conventional means, and once again environment has a definite role to play in exactly what constitutes a critical ratio of rate/yield. It has been shown that one of the consequences of mitochondrial variation across species is that the rate vs. yield of oxidative phosphorylation varies slightly, and in no species is it set up for highest possible yield (Pfeiffer, et al. 2001).

The important thing to remember here is that evolution is an environmentally-dependent and path-dependent process. Just because it has accomplished a specific end in a certain way, does not mean that was the only solution (or even the best one).

Sources & Further Reading

Written by Caudoviral

03/09/2011 at 18:54

Posted in Biology

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Mitochondria are Weird

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Let’s get one thing straight: I like my mitochondria. They are a necessity for eukaryotic life (although there have been some theories about alternate high yield ATP production pathways or schemata of power management). But for all that…dang are they weird.

The situation is basically a symbiosis event. At some point the ancestor of eukaryotic cells engulfed a prokaryote (most likely Rickettsiales). However, instead of being broken down into constituent molecules, this prokaryote persisted, reproduced, and evolved within the cell. One of the most fascinating things about this arrangement is that, as time went by, the mitochondria actually began to outsource their genome to their host. This is debatably the point at which they completely lost their independence and became organelles as opposed to organisms.

The human mitochondrial genome is 16,568 bases and contains no introns. It codes for about 37 genes, a fraction of what the organelle actually requires. The rest of the proteins are made from your nuclear DNA and imported through an annoyingly complex transport system. As we look across species, we can see that the mitochondria in different organisms have retained more or less of their original genome (e.g. plasmodium have 5 genes in their mtDNA and reclinomonas have 98 genes), but no organism retains completely independent mitochondria. And there are a lot of extra tricks that the genome picks up across species: sometimes linear, sometimes circular, sometimes with introns, sometimes not, multiple copies of the genome per mitochondria, etc. As an added bonus you can wind up with multiple mitochondria per cell with multiple different genomes in that mitochondrial population.

The practical side of this is that inheritance of mitochondrial disorders is emphatically not Mendelian, and tracking such disorders can be all sorts of a headache. A headache we are going to have to work through if we want to effectively study and prevent these diseases.

Sources & Further Reading

  • I highly encourage anyone with a background in genetics and some time to kill to go take a look at MitoMap. It’s the human mitochondrial genome database and includes some great references.
  • One of my commenters has recommended Nic Lane’s Power, Sex, Suicide: Mitochondria and the Meaning of Life, although I personally can’t speak as to whether it is good or not. Am looking for a copy but even if I find one it will have to wait its turn in a long line of reading material.
  • And because spec-fic is fun I find myself compelled to recommend Parasite Eve both the novel by Hideaki Sena and the PS1 game put out by Square. Nothing approaching scientific accuracy, just plenty of “What if mitochondria were an evil hive mind?” lovelyness and body horror. There is also a movie, but I hear that it wasn’t that great.

Written by Caudoviral

03/07/2011 at 14:09

Posted in Biology

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