Archive for the ‘Health’ 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?
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
It has been pointed out to me that if I am going to spend time talking about HIV latency, it might benefit my readers to understand what is meant by that. And to understand that, you need a basic understanding of the disease. So here it is, your crash courseon the course of HIV infection and viral latency.
Untreated HIV infection can be split into roughly three phases:
- Initial Infection and Acute Symptoms: This phase represents the 1-2 months immediately after infection. The virus integrates into your cells and provokes an immune response. This leads to flu-like symptoms that do not persist.
- Asymptomatic Phase: During this phase, which can last ~2-10 years, you have a relatively low viral load and demonstrate no symptoms. This is because the immune system is still in control. The virus is not causing CD4 T-cell death at an unmanageable rate and this phase persists until an immune escape event occurs.
- AIDS: Once the virus dodges immune control, it proliferates rapidly, killing CD4 T-cells and opening the body up to the spectrum of opportunistic infections that will ultimately lead to death.
HAART (Highly Active Anti-Retroviral Therapy) can essentially prolong the asymptomatic phase of the infection indefinitely (or at least for as long as your body can deal with taking the drugs). The problem is that during the asymptomatic phase, your body is not able to eliminate the virus entirely. And even on HAART the drugs only work for as long as you take the drugs. So despite reducing viral load to a minimum, neither your body or our current best therapy can provide a cure. Just a stopgap. And it is a stopgap that has allowed uncountable numbers of HIV patients to live longer and better quality lives, but it is ultimately not a solution to the underlying problem.
So how is it that HIV can hang on long enough to eventually overpower the immune system? And how is it that our effective anti-retroviral regimen can’t manage to destroy the infection entirely? Viral latency. HIV has a number of molecular mechanisms (primarily based on transcription control) that allow it to sit in a cell for a good deal of time before replicating and budding off to go along its merry way. When that quality is coupled with the quirk of certain T-cells to go latent and become memory-T-cells, it makes for a particularly stealthy infection. The body and the drugs can do nothing to a latent virus in a latent cell, but if either of them let their guard down, and that cell becomes active and that virus becomes active, the entire infection can re-profuse.
This is (hopefully) the last hurdle to achieving an effective and practical cure for the disease: find a way to dump the reservoirs. Preferably without killing the patient. If only that were as easy as it sounds.
Females infected with HIV proceed to AIDS faster than their male counterparts. This is, ironically enough, one of the benefits of being a pre-menopausal female at work. As I explained earlier, there is a recognizable gradation in survival value between pre-menopausal females, males, and post-menopausal females based on reproductive capability. You can’t properly gestate a child for 9 months if you are dead. To this end there are several health benefits exclusive to the pre-menopausal female system.
Or rather, they would be benefits were it not for the nature of this virus. Now, in HIV’s defense, this is not actually of selective benefit to it. Viruses aren’t out to kill us and in fact doing so prevents them from going about their merry business of infecting more hosts. What happens is that the HIV latency period relies on its ability to go dormant in inactive immune cells, but in these female patients there is a generally higher level of immune activity. This means fewer inactive cells overall, fewer places for HIV to hide, yet unfortunately not enough immune activity to actually eradicate the infection. The end result is that the patient’s immune system takes more wear and tear than her male counterpart’s, the higher rate of cellular activity leads to higher viral activity, and she progresses to AIDS significantly faster.
Notably this sort of thing is also implicated in the higher rate of auto-immune disease in the female population.
Just as a note, you can probably expect a lot more HIV latency articles throughout the rest of the semester. Have just started research on it, I should be dredging up all kinds of interesting stuff from the literature.
Sources & Further Reading
- “The X-files in immunity: sex-based differences predispose immune responses.” Fish Nature Reviews Immunology 8 737-44 (2008)
- “Sex differences in longitudinal human immunodeficiency virus type 1 RNA levels among seroconverters.” Sterling, et al. Journal of Infectious Diseases 180 666-72
- “Sex differences in HIV-1 viral load and progression to AIDS.” Farzadegan, et al. Lancet 352 1510-14 (1998)
Someone recently said to me that telomerase wasn’t oncogenic. And in one sense, they were exactly right: the gene that produces telomerase is not recognized as an oncogene. In the other sense however, they were wrong: the reactivation of telomerase (or ALT) is a necessary step in the route to a malignant neoplasm, known as oncogenesis. This is one of the reasons I have never liked the “oncogene” designation. It’s fuzzy and a little misleading. Moreover, I think this fuzzyness is related to some of our misconceptions about cancer.
When we look at disease, we tend to look at it in terms of cause and effect. E.g. influenza causes flu, pneumocystis causes pneumonia, etc. And this schema works really well when you a are dealing with pathogens. Charge in, antibiotics and antivirals blazing, remove the cause, and the disease goes away (usually, although if it doesn’t then you probably have just not removed the cause well enough, as is the case with latent HIV). However, cancer and genetic diseases are often a different story. People ask: “Why haven’t we cured cancer yet?” and I have seen at least one paranoid documentary claiming we could obviously cure cancer at any time and just don’t because evil corporations profit off of it. Ideas like these are the result of the misconception that cancer has simple causes and simple solutions.
Misconception concerning oncogenes is a primary culprit in the current confusion, and (as I talked about in an older post) why we tend to hear a lot these days about “the X cancer gene”. These ideas are absurd. There are two mistakes working together here: (1) That oncogenes are genes whose only purpose is to cause cancer; (2) That oncogenes are sufficient to cause cancer.
(1) In truth, oncogenes have a variety of roles in the body, it is their constitutive over-expression that drives the growth component of cancer. Many oncogenes are lethal if knocked out, which is to say they are vital to development and survival of the whole organism. It is just that there is actually to much of a good thing.
(2) This is where things really begin to go off the rails. An oncogene alone is no more a cause of cancer than active telomerase or the lack of a tumor suppression gene. The development of a neoplasm is a stepwise process and no one step is sufficient while all of them are necessary. Generally it requires three mutations for a benign neoplasm and five for a malignant one (certain conditions, like a genetic predisposition for retinoblastoma or infections with an oncovirus take this number down by one). And while these mutations need to perform similar functions (cause growth, remove reproduction limits, direct angiogenesis, alter metabolism, etc), they can occur in any of a multitude of individual genes.
With a system so complex, it should be apparent why the old schema doesn’t work. There is no one single cause of cancer and no one single cure. There is no one “X cancer gene”. Cancer is a large spectrum of conditions the battle against which will rage on well into the future. While we might find ways to cure specific cases and deal with specific oncoviruses and genetic predispositions we will never cure ‘cancer’. To do so would mean to remove all mutation and make ourselves essentially genetically static. I hope I don’t have to explain why that would be a bad thing.
Sources & Further Readings
- I don’t really have a whole lot on oncogenes lying around at the moment, but a nice place to get an introduction might be Geoffrey M. Cooper’s textbook on the subject. It’s short and pretty straightforward.
Fair warning: the following is sexist in the way only evolutionary biology can be.
Females are, individually, more valuable than males. Until they hit menopause that is (at which point they become worthless). This is how our bodies work, don’t shoot the messenger. As manifestation and proof of this concept we can examine susceptibility to cardiovascular, cerebrovascular, and metabolic diseases. In order of least to greatest risk: pre-menopausal females -> males -> post-menopausal females. From the standpoint of passing on genes, it is important for females to be able to stay healthier for the span of time necessary to produce offspring, for as long as they are offspring production capable. After that point, the body stops caring. But don’t worry, scientists don’t.
Researchers like Deborah Clegg are working quite hard to understand what exactly happens at that crucial dividing line. The most obvious change? A stiff decrease in the amount of estrogen in the body. Okay, but how does that affect health? Glad you asked. I just had the pleasure to sit through a lecture given by Dr. Clegg, and it provided several fascinating insights:
1) Metabolic activity, hunger response, and eating behavior is largely controlled by a protein known as leptin. When you give excess leptin to pre-menopausal females it prompts a dramatic change in their eating behavior (and possibly metabolism) that leads to weight loss. No such similar response exists in males or post-menopausal females. Interestingly, we have known about the general effect of leptin for ages, although the male/female divide is new info (New info that makes it seem pretty silly that when drug trials were done on leptin to see if it could be used as a diet pill they used an all male test group. Missed opportunity that.)
2) This sex-specific/age-specific behavior is because estrogen is a necessary co-factor in leptins function. Estrogen both is necessary for the transport of leptin across the blood brain barrier and the activity of nuclear estrogen receptors increases production of leptin receptors. There are a number of ways to demonstrate how critical estrogen is to this, but perhaps the best is that if you give males or post-menopausal females estrogen injections, it allows for the response to leptin seen in pre-menopausal females.
3) Hormonal birth control can mimic some of the effects of menopause. By suppressing the normal ovulatory cycle and exchanging the peak of estrogen activity during ovulation for a regulated, lower estrogen level, the door is opened for the flood of nasties that most females shouldn’t have to worry about until after their child-bearing days are over. Indeed, Dr. Clegg’s data suggest that in the absence of prevalent hormonal birth control, there would be little to no obesity or obesity correlated illness among pre-menopausal females. Of course, my common sense suggests that there might be a little bit of a trade-off here, and that a few extra pounds could beat a baby in the cost/benefit analysis.
Afterthought (2/11/2011): Corrected some typos. It occurs to me that I should, for the sake of clarity, note that the above applies in mice/humans, it probably extends to other animals but probably not beyond mammals. Maybe not even beyond placental mammals.
Sources & Further Reading
- Once again this is based on the fascinating research of Deborah Clegg, whose recent publication list is available here
- Dr. Clegg will be appearing in a 2012 documentary on the obesity epidemic in America, although I was remiss in not catching the name.