Archive for the ‘Science’ Category
One of the more common misnomers flying around the pop-sci publications is this idea of “Junk DNA”. Now to be fair, this label originated with the scientific community. Even Francis Crick was dismissive of its utility, but that was thirty years ago. As it turns out, junk DNA (more accurately called non-coding DNA) contains both a variety of sequences with biological utility and large portions of our genomic history. It is the later that I wanted to bring up today.
One of the major forms of transcriptional control involves histone deacetylase. You can think of histones as essentially spools of DNA. If DNA is wrapped tightly around histones it is unavailable to be transcribed to RNA and then translated to protein. Modification of histones determines the precise manner in which the DNA interacts with them, and acetylation of histones loosens the wrapping of the DNA, making it available. So your cells employ histone deacetylase to make sure that regions of the genome stay nice and silent. Which is good, cause there is some scary stuff hiding in the sea of non-coding DNA.
Recently there has been a push to use histone deacetylace inhibitors to cause expression of genes of interest (e.g. it is suggested they could be used to flush latent virus out of memory T-Cells to destroy latent reservoirs of HIV). Now, these ideas seem really sound on the surface. If we could destroy that reservoir of latency, we could see long-term drug free remission in HIV infection. But what else might you wake up? As far as I know there is no reliable method (if there is indeed a method at all) to target histone deacetylase inhibitors to specific regions of the genome, so this would be a general approach inhibiting all of a cells histone deacetylase, which I can’t but think would lead to A) steps towards tumor transformation as cell cycle controls were disabled, and B) the activation of unfriendly endogenous elements in the genome. Fishing out integrated HIV provirus is an excellent idea, but what else might we pull in with it?
This is just a heads up that a new site has been added to the ‘Resources’ links down there on the bottom right. I was trying to look up something about mitochondrial fusion proteins and kind of stumbled across a site that hosts a number of very interesting science videos. Despite the name, DNAtube appears be a multidisciplinary site hosting videos on all aspects of science and math. Probably worth checking out, I know I would be if I had time to take a study break.
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.
- 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
- HIV-1 Utilizes the CXCR4 Chemokine Receptor to Infect Multipotent Hematopoietic Stem and Progenitor Cells (Carter, et al. 2011)
- Thats only the second Highlander joke in three months of science blogging. I am falling behind schedule.
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
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.
When I study retroviruses I always feel a little like I am studying something closely related to myself. Why? Well, because I kind of am. See, the human genome is not exactly virginal, and over our development a number of retroviral hangers-on have integrated but never left.
One of the characteristics of a retrovirus is that it converts its genome from RNA to DNA and then places that genome into our own. So the idea is that we replicate the viral proteins just as we replicate our own cells. However, not all viruses wind up extracting themselves, and those that don’t become what we call endogenous.
They stay with us, for good or ill, and get passed through each generation, becoming part of us. So when we look at something like HIV we also have to realize that retroviral envelope proteins were essential in mammalian placental development. And that it was the retroviral env proteins that kept us alive when our mothers immune system would have otherwise killed us in utero. A discomfiting thought.