Communicating Science Course 2012 Blogs
How the Dead Speak: Splicing together history, medicine and biology
By: Makoto Ohira
On the night of July 16, 1918, Bolshevik secret police led by Tsar Nicholas's chief executioner, Yakov Yurovsky, shot the Romanov family in a small basement cellar: Nicholas II and his wife Alexandra; their daughters Olga, Tatiana, Maria, and Anastasia; and their youngest and only son, 14-year old Tsarevich Alexei. Yurovsky and the Bolsheviks buried most of the family and their servants in one shallow grave, and then burned and buried Alexei and Maria’s bodies elsewhere. Lenin’s will was done. World War I still raged and the Soviet Union emerged soon after like a great black moth from a bloody cocoon.
We know the back-story. Queen Victoria passed along a mutant gene for hemophilia through her nine children and 34 grandchildren, most of who married into the many noble families throughout Europe. Victoria's granddaughter, Princess Alix, married the ill-fated Nicholas Romanov and took the Russian Orthodox name Alexandra. Alexandra passed the bleeding disease to her son Alexei and turned in distress to a wandering monk named Rasputin to ease her son's suffering.
In July of 1991, two amateur historians discovered a shallow grave twenty miles from Ekaterinburg where the Romanov family was murdered. Russian archaeologists examined the remains and tentatively concluded that they belonged to the Tsar, Tsarina, three of their five children, and their servants. In 1992, a British forensic lab used DNA fingerprinting technology like crime scene investigators to confirm that the remains belonged to the Romanovs and their attendants.
In July of 2007, archaeologists discovered another shallow grave not far from the first. DNA analysis, this time at the University of Massachusetts Medical School (UMMS), showed that the burned bone fragments from the second grave belonged to the remaining Romanovs, Alexei and Maria.
The team from UMMS then continued digging into the DNA evidence to see what they could uncover about Alexei’s hemophilia. They found that Alexei suffered from a severe form of the disease called hemophilia B or Christmas disease, named after a 5 year old boy whose disease British physicians first described in 1952. Christmas disease results from defective coagulation factor IX, one of the proteins made by our body that is necessary for blood clotting.
The UMMS team specifically found, using the more advanced DNA sequencing technology available in 2009, that Alexei had a single-letter mutation of the F9 gene. They then used an artificial gene containing Alexei’s specific mutation to show that the single-letter change caused his cells to misprocess the genetic code, resulting in defective factor IX.
The cellular process that went awry is called splicing, a key step in how our cells make protein. The instructions for all the proteins in our body are encoded among the billions of letters that comprise the long strings of DNA in our chromosomes. These chromosomes reside in the nuclei of our cells. To make protein, enzymes first transcribe the DNA code into shorter RNA messages. Then these messages shuttle out of the nucleus into the main compartment of the cell where other enzymes translate them into proteins like factor IX.
Bacteria make protein by following the same essential steps: DNA to RNA to protein. More complex organisms add a step within that sequence: splicing. During splicing, the RNA is diced and reattached in new orders. Splicing occurs because non-coding segments interrupt the protein-coding parts of DNA. Biologists call these interruptions introns, and the protein-coding parts exons. Enzymes copy both the introns and exons from the DNA to the RNA. Before protein production from the RNA template, splicing removes the introns and stitches the exons together to make a continuous and correct message.
A large, complex molecular machine known as a spliceosome does the splicing. The spliceosome recognizes short codes in the RNA messages that identify the introns, and then does the cutting and splicing.
When scientists recognize biological features retained from an ancestral species, they call it “conserved”. We know, for example, that rodent and human hands are conserved structures from evidence like fossils, embryonic development, and the protein signals that tell limbs how to form. Biologists know from genetics and biochemistry that the spliceosome was conserved through the billion years of evolution separating single-celled yeast from humans. Something so deeply conserved must be important.
Why is splicing important? Hints first emerged from the human genome project. DNA sequencing during the 1990s shocked scientists when they found that humans had about the same number of protein-coding genes as flies. How could that be? Eventually, additional information emerged: more human genes contain introns than do the genes of less complex animals; humans have longer introns than less complex animals; and human genes splice into more protein types than those of less complex animals. Introns therefore explained the unexpected scarcity of human genes: each gene splices in a mix-and-match process into many protein variants.
More evidence of splicing’s importance comes when the splicing machinery goes awry. We know today that splicing errors are linked with half of all disease-causing genetic mutations, including everything from atrophy to deafness to cancer.
Alexei had a single mutation that shifted one of the splice sites, which tell the spliceosome where to cut, and that shift caused defective factor IX protein. The defective factor IX meant that Alexei's blood would not clot normally, and every cut and bruise from childhood play led to life-threatening bleeding. Alexandra’s care and worry and Rasputin’s dubious ministrations kept Alexei alive for fourteen years. Today, patients suffering from Christmas disease can inject recombinant factor IX to control the bleeding.
We know now that the fundamental process of splicing drives the biological complexity showcased in humans. But complexity comes with a price. When the splicing machinery consistently errs, human suffering or death often ensues. Alexei inherited from Queen Victoria, through his mother, a single letter mutation in his factor IX gene that caused an error in splicing, and ultimately his hemophilia. UMMS researchers made this precise diagnosis almost one hundred years after the murder of Alexei and his family by analyzing fragments of burned and broken bone.
Reviving failing hearts: generating healthy heart muscles from scar tissue
By: Ogooluwa Ojelabi
Due to the limited ability of the heart to regenerate, injury such as heart attack typically causes permanent damage to the heart. A single episode of heart attack can wipe out more than twenty-five percent of the heart muscle cells – cells responsible for the beating of the heart – within a few hours. Damaged heart muscle cells are usually replaced with scar-forming cells instead of muscle cells during the healing process. Formation of scar tissue in the heart reduces the heart’s ability to pump blood efficiently, and this can ultimately results in heart failure. According to the American Heart Association, more than five million people in the United States experience heart failure annually. Heart disease alone causes more deaths in the United States than all forms of cancer combined.
While there are currently a wide range of therapies and medications used to treat heart failure, a major goal in cardiovascular research is to prevent or treat heart attack by regenerating heart muscle cells after injury. By studying the hearts of different organisms ranging from small insects to larger animals such as pigs and horses, scientists have made significant discoveries over the past few decades on how to replace damaged heart muscle cells. Each of these discoveries brings us closer to finding efficient ways of reviving the failing heart.
Eric Olson and his group at the University of Texas Southern Medical School recently reported another major stride towards repairing injured hearts. By introducing four genes into the hearts of live mice that had suffered a heart attack, these researchers converted scar tissues in the mouse heart into healthy and functional heart muscle cells.
These four genes, collectively referred to as GHMT, normally direct heart formation in the early stages of development of embryonic mice – or humans, just before birth. Olsen and colleagues delivered these GHMT genes into the injured portions of mouse hearts with the aid of innocuous viruses that can insert genes into actively reproducing cells, such as the heart’s scar-forming cells, but not the non-reproducing heart muscle cells. As described in the May 31st issue of the Nature journal, GHMT transformed scar tissues into functional heart muscle cells within a month. About three months after treatment, the hearts of mice that received GHMT beat more strongly and pumped more blood than those of their counterparts that also suffered heart attacks but did not receive GHMT.
This study built on previous findings that showed GHMT genes can transform scar-forming cells, grown in petri dishes in the lab, into heart muscle cells. Experimental advances in petri-dishes don’t always work out the same way in real animals, because the native environment in live animals is very different from the artificial environment created in the lab. So, that the GHMT can transform scar-tissues into heart muscles in both the lab environment and in real animals is very exciting. However, scientists need to be absolutely sure of the safety of the viruses used to deliver the GHMT genes into live animals, before using this approach in humans. Although, this discovery may not immediately translate into therapies for treating heart failure in humans, it opens up an entirely new approach to regenerating damaged muscle cells after a heart attack.
Other groups are trying to regenerate damaged heart muscle cells with the help of stem cells – amenable living cells that can be directed to form a specific cell type of interest. Scientists have found ways of making stem cells out of skin cells taken from patients, and then directing these stem cells to form heart muscle cells in the laboratory. However, placing heart muscle cells made outside the body back into the heart has proved difficult. The viral delivery of GHMT genes approach described by Olson and his colleagues circumvents this problem, in that scar cell remodeling takes place inside in heart rather than in the petri dish. This advance may ultimately make it possible for heart muscle regeneration to take place in a clinical setting.
Despite the promise of this study, many unanswered questions need to be addressed before heart disease patients can start reaping the dividends of this new approach. How exactly does the observed improvement in heart function happen? What are the risks of this approach? And how might this finding translate to therapies for preventing heart failure in humans? Scientists are relentless in their quest to address these questions, but the advance made by this study represents a giant stride towards developing an efficient and inexpensive way of treating patients after a heart attack.
Kunhua Song, Young-Jae Nam, Xiang Luo, Xiaoxia Qi, Wei Tan, Guo N. Huang, Asha Acharya, Christopher L. Smith, Michelle D. Tallquist, Eric G. Neilson, Joseph A. Hill, Rhonda Bassel-Duby & Eric N. Olson. Heart repair by reprogramming non-myocytes with cardiac transcription factors. Nature. 485: 599–604
You Can Quit Smoking – And This Friendly Virus Can Help
By: Samantha Palace
A team of scientists at Cornell University wants to cure your smoking habit with just one shot.
Although tens of millions of adults in the United States smoke cigarettes on a regular basis, most of them – nearly 70%, according to the CDC – want to quit. Half of all smokers will try to quit this year. By and large, they won’t succeed.
Why do they fail? Enormous anti-smoking campaigns have saturated the media. We all know, by now, that if we give up cigarettes we can save money, smell better, and improve the health of ourselves and our children. New support groups, prescription drugs, and over-the-counter nicotine replacement chewing gums blossom before our very eyes: an entire industry flourishing as smokers repeatedly try, and fail, to quit.
Many would-be quitters can be thwarted by the fact that, although they’ve made up their minds to stop smoking, their bodies aren’t always on board. So while an aspiring ex-smoker might have a negative emotional response to cigarettes, their body rewards them for smoking with calmer nerves and sharper senses. If consumers could choose to eliminate these mixed messages, squashing their positive physiological response to tobacco products, they might find it easier to quit.
Martin Hicks, Ronald Crystal, and their colleagues at Cornell University are developing technology that could ultimately allow smokers to ensure that cigarettes don’t continue to charm their bodies in spite of their brains.
Tobacco contains a small molecule called nicotine, which produces the famous feel-good effects that lead to addiction. When nicotine binds to a certain receptor in the brain, it signals the brain cells to start producing dopamine. Dopamine makes us feel more relaxed, more aware, and happier; and this nicotine-induced dopamine production largely accounts for why cigarettes are so difficult to give up.
By interfering with nicotine’s chemical effects in the brain, Hicks and co-workers hope to separate tobacco consumption from dopamine payoffs. In their recent article, published in Science Translational Medicine, they describe a treatment that allows mice to produce antibodies that recognize nicotine in the bloodstream. These antibodies act like a sponge, binding to nicotine molecules and preventing them from leaving the bloodstream and entering the brain.
Scientists have tried this kind of antibody-based approach before in their attempts to protect the brain from the effects of nicotine. Some groups have managed to block nicotine from reaching the brains of mice by injecting the mice with pre-made nicotine antibodies. Others have developed nicotine vaccines, which train the immune system to produce its own nicotine-binding antibodies. Versions of these vaccines are undergoing clinical trials. Both of these methods, however, have significant drawbacks. Preliminary results indicate that the nicotine vaccine is safe, but not very effective: most smokers who received the vaccine in clinical trials didn’t have any more luck in quitting than their non-vaccinated counterparts, probably because they don’t end up producing high enough levels of antibodies. And any smoker looking for help from pre-made antibodies would have to submit to a long course of frequent injections – not a very appealing option.
Hicks’s group has a third way of introducing nicotine-binding antibodies: they’re using the technology of gene therapy. Gene therapy allows scientists to deliver custom-made genes into the cells of adult animals – and humans. Traditionally, this technology is used to treat genetic diseases by supplementing a patient’s missing or mutated gene with a functional copy. Hicks and colleagues used it to give mice the genes they needed to produce antibodies that effectively bind and sequester nicotine.
These genes provide blueprints for building nicotine-specific antibodies, but they only work from the inside of a cell, and it isn’t easy to get them there. Mammalian cells don’t normally take up extra DNA – they already contain all of the genes that they need. In order to get past this particular barrier, scientists rely on a little help from a virus called adeno-associated virus, or AAV.
As a virus, AAV specializes in getting DNA inside of mammalian cells. In nature, it usually puts copies of its own DNA into cells; but scientists have engineered special, non-infectious strains of AAV that will deliver any piece of DNA you like for use in gene therapy. Unlike many viruses, these strains will neither kill cells nor make more viruses. They carry out a one-way mission: they deliver genes to target cells, and then benignly fade away.
The group at Cornell used one such AAV strain to deliver nicotine antibody genes to mice. This method of delivery resulted in the sustained production of large amounts of antibody, overcoming the primary drawback of the existing vaccine-based therapy. When mice are dosed with nicotine, the drug usually travels to their brains, causes the production of dopamine, and results in slowed heart rate, lower blood pressure, and decreased movement. Mice that were treated with the AAV strain seemed resistant to the physiological effects of nicotine: when they were injected with nicotine, most of it stayed in the blood rather than traveling to the brain, and the mice didn’t display measurable symptoms of excess dopamine release.
This study hasn’t shown that the AAV-treated mice would choose to consume less nicotine, if they were allowed dose themselves. Nor do the authors guarantee that the same approach would necessarily work in humans – that research still needs to be done. Still, this work could serve as the foundation for an effective technology that takes the chemical allure out of tobacco consumption. And with that tool in hand, some smokers could find themselves one step closer to quitting for good.
M. J. Hicks, J. B. Rosenberg, B. P. De, O. E. Pagovich, C. N. Young, J.-p. Qiu, S. M. Kaminsky, N. R. Hackett, S. Worgall, K. D. Janda, R. L. Davisson, R. G. Crystal, AAV-Directed Persistent Expression of a Gene Encoding Anti-Nicotine Antibody for Smoking Cessation. Sci. Transl. Med. 4, 140ra87 (2012).
Australopithecus sediba – A missing link in our origins
By: Harish Palleti Janardhan
We as humans have been curious about understanding our origins since time immemorial. This quest has been, to an extent, satiated by the discovery of a number of hominid fossils over the last century.
Recently, Dr. Lee R. Berger, Professor in the Institute for Human Evolution at University of Witwatersrand, South Africa and colleagues discovered fossils at the Malapa site in South Africa. The fossils, encased in cave deposits, include partial skeletal and cranial (skull bone) remains of two individuals. One of the fossils is a juvenile and labeled as Malapa Hominin 1 (MH1). Malapa Hominin 2 (MH2) is the other fossil discovered, the remains of which were located in close proximity to MH1. MH2 is an adult with remains of upper teeth, parts of the lower jaw and parts of the skeleton. The MH1 fossil included a partial cranium in addition to a fragmented lower jaw and parts of the skeleton. Further, based on features of the mandible and shape of the pelvis, the researchers conclude that MH1 was a male and MH2 a female and that the overall level of sexual dimorphism is similar to that of modern humans.
Since the discovery of the fossils in 2008, the investigators studied various aspects of the fossil bones over a period of two years to describe, accurately, the fossil finds. The partial remains of MH1 were used to describe the holotype. The holotype is a term that refers to the exact physical specimen used to describe a species for the first time. Based on their work, Berger and colleagues came to the conclusion that the fossils represent a novel species that existed about 1.95 -1.78 million years ago and exhibit characteristics in between that of the genus Australopithecus and the genus Homo, to which we belong. However, they placed the fossils within the genus Australopithecus based on key findings such as a limited cranial capacity, small body size, and long upper limbs amongst other primitive features they share with the genus Australopithecus. Due to the numerous similarities in various features of the cranium and skeleton, the closest species to A. sediba, the species name given to the new fossils, is Australopithecus africanus. The latter is a species that existed around 3 million years ago and pre-dates A. sediba.
More recently, in a podcast interview to the journal Science that accompanies additional published findings, Berger and his colleagues describe the Malapa site discovery as the “Rosetta stone that unlocks the understanding of our genus, Homo”. Berger and colleagues make two interesting inferences from their extensive study of the fossils including that of an alternative hypothesis to the origins of the genus Homo. The traditional view is that during the path from A. afarensis to H. habilis and H. erectus, the brain got increasingly bigger before changes occurred to the primitive skeleton. However, based on the new findings, it appears that there were significant changes to different aspects of the cranium and the skeleton all along. Further, based on advanced synchrotron imaging of the skull of A. sediba at a resolution of 6 microns, the investigators infer that there was significant reorganization of the brain such as an enlargement of the Broca’s area for speech. The latter results together with the findings of the presence of an anatomically advanced Homo - like hand in A. sediba, suggests that the traditional view of encephalization or brain enlargement occurring before brain reorganization in human evolution may not be right.
Finally, the researchers suggest that with the discovery of A. sediba, there is some uncertainty in the phylogenetic relationships and placement of earlier discovered hominid species such as Stw53, OH62 and KNM-ER 3735 in the category of Homo habilis. This is because Stw 53 appears to be primitive to MH1 and hence may in fact belong to A. africanus. Since the positions of OH62 and KNM-ER were placed in the evolutionary scale based on the position of Stw 53, the former fossil positions also become uncertain. In addition, the researchers could not determine the exact position of A. sediba in relation to each species of the genus Homo, except to state that A. sediba may “represent a candidate ancestor or a sister species to a close ancestor of our genus Homo”.
1. Lee R. Berger et al. Australopithecus sediba: A New Species of Homo-Like Australopith from South Africa. Science 328, 195 (2010)
2. Science Podcast - September 8 2011
Good news for smokers: nicotine may help protect you from Alzheimer’s disease
By: Alison Philbrook
Many of us know someone affected by Alzheimer’s disease, a serious neurodegenerative disorder that affects memory, thinking, and behavior. There is no known cure, and managing symptoms and slowing the progression of the disease is often very difficult. An estimated 5.1 million Americans currently struggle with this disorder, a number that will only increase as the baby boomer generation continues to age. What you may not know is that smokers are less likely to develop Alzheimer’s disease compared to nonsmokers. This topic, however, is heavily debated in the neuroscience community. One lab from the Republic of Korea argues that nicotine, the principal ingredient in cigarettes, may actually have some health benefits.
While the cause of Alzheimer’s disease is still an area of research, the disease is associated with the accumulation of plaques and tangles in the brain. Plaques consist of protein fragments in the gaps between nerve cells, while tangles build up inside cells. Yong Kim’s lab based at KonKuk University created a mutant mouse model that develops these accumulations and later display deficits in memory and behavior, similar to human Alzheimer’s patients. The researchers treated the mice with low, average and high doses of nicotine for six months by adding the drug to their drinking water. After the six-month period, the researchers then tested the mice on their cognitive performance.
To test for cognition, the researchers used what’s called a water maze test. This test is exactly what it sounds like; mice are placed in a pool of water and have to find a destination point. Specifically, mice are placed in a circular pool with a small platform hidden in cloudy water. Since mice dislike being in the water, they will swim until they find the hidden platform and spend the majority of their time on the platform until the end of the test. Before the researchers start the assessment, they pre-train the mice in the pool until the mice reliably find the platform. After the nicotine administration, the researchers then test the ability of each mouse to remember where the hidden platform is in the pool. The maze is commonly used in behavioral neuroscience as a measure of learning and memory.
To measure performance in the water maze, a computer program recorded the distance swum, swimming speed, swimming pattern, and escape latency. These values measure the ability of the mice to remember the location of the platform (specifically measuring spatial memory) and swim the correct path to the platform. The results were clear: the more nicotine the mice received, the better they performed on the test. After the experiment, the brain tissue was removed from the mouse and researchers stained for a specific protein called an α7 nicotinic acetylcholine receptor. Human patients with neurodegenerative diseases tend to have decreased amounts of these receptors. The mice receiving nicotine treatment, however, showed increases in the amount of this receptor. The researchers suggest that this increase in α7 nicotinic acetylcholine receptors is correlated with the improved memory performance seen in the water maze test.
This is not the first study to suggest a role for the α7 nicotinic acetylcholine receptor in learning and memory. Mice lacking these nicotinic α7 receptors (called “knockout mice”) show impairments in memory function, while drugs that act on these receptors improve learning, memory, and attention . Thus, it seems that α7 nicotinic acetylcholine receptors play a role in learning and memory and that nicotine helped our furry friends improve memory performance by boosting the amount of these receptors in their brains.
It is important to take these findings with a grain of salt. According to the American Cancer Society, nearly half of all long-term smokers will die from a tobacco-related illness. Smoking increases the risk of lung cancer, heart attack, stroke, and other cancers. The benefits of smoking still don’t seem to outweigh the risks. If scientists can create a safer drug that affects these nicotine receptors there might be hope for treating and/or preventing Alzheimer’s disease. Indeed, some researchers are pursuing cotinine, the main metabolite of nicotine, as a potential therapeutic agent against Alzheimer’s disease . Since cotinine is non-addictive and safe, we will likely see some form of this drug used to treat Alzheimer’s disease in the future.
Original Article: Shim, et al (2008) Nicotine Leads to Improvements in Behavioral Impairment and an Increase in the Nicotine Acetylcholine Receptor in Transgenic Mice. Neurochem Res 33: 1783-1788.
 Levin, E (2012) α7-Nicotinic receptors and cognition. Current Drug Targets 13(5): 602-6.
 Echeverria, V., & Zeitlin, R (2012) Cotinine: A Potential New Therapeutic Agent against Alzheimer’s disease. CNS Neurosciences & Therapeutics 18(7): 517-523.
Hardwired to sniff out tasty food?
By: Michael Purcaro
While Aesop would have us believe only ants store food, a wide variety of creatures will instinctively build food caches for the harsh winter months. You may have witnessed an idyllic scene of squirrels running about, their cheeks stuffed with nuts, filling their underground coffers full of morsels. You might have wondered, though, how do the creatures find viable food, or locate it later under the cover of snow? As it turns out, the unique aromas different foods give off may invoke memories and emotions in small mammals—not unalike how the smell of chocolate-chip cookies can remind us of grandmother’s cooking. According to a recent article in the journal Behavioural Brain Research, rats exposed to the smell of almonds activate parts of their brain associated with “learning and memory and the processing of emotional stimuli.” In fact, only the smell of almonds stimulated the rat brains in this manner; the smells of banana, rose, or citrus failed to activate as much rat neural circuitry. Surprisingly, almonds stimulated rat memory and emotional centers even in rats that had never been exposed to almonds before. This was even true for rats born to families that hadn’t been exposed to almonds for several generations. For humans, this would be reminiscent of being born in a world stripped of baked goods for more than a century, yet still instinctively knowing the smell of great-great-great-grandma’s cookies indicated something delicious!
The team of researchers from Northeastern University and Worcester Polytechnic Institute utilized functional magnetic resonance imaging (fMRI) to study the rodent aroma responses. In normal MRI, the MRI scanner, a powerful electromagnet, generates strong magnetic fields which align some atomic nuclei in the organism being scanned. Radio frequency fields (not unlike FM radio signals) then disturb this alignment, and cause the nuclei that move to produce their own little magnetic fields. The MRI scanner can detect these small fields, and, after some computation, produce a stack of 2D images. fMRI imaging works in a similar fashion, but focuses on the magnetic field differences that exist between red blood cells with all their oxygen, and red blood cells whose oxygen was consumed by the brain. fMRI images show areas of increased oxygen consumption, and thus areas of increased brain activity.
When starting the image study, the researchers were expecting to find the standard “odorant code”—a normal sequence of neural firing events starting with receptors in the nose and ending in a particular part (the olfactory bulb) in the brain. This normal odorant code was confirmed for banana, rose, and citrus. They were startled to discover the “dramatic difference” that almond produced—the fMRI showed a wide-spread activation of neurons in memory areas, suggesting that rats were hardwired to find buried stores of high-calories nuts. The fMRI results were collaborated by the extra time the rats spent sniffing the source of the almond smell (a chemical call benzaldehyde, the major ingredient in almond oil).
The study results may help prove theories of how the human brain works. In particular, the areas of the rat brain excited by the almond smell parallel an area of the human brain theorized as responsible for emotion. This so-called “Papez circuit” in humans could be the area that assigns emotional value to things in the environment. At the most primitive level, this could be the area that programmed humans to locate food, select mates, and identify predators. We even may be hardwired to know what smells indicate high-energy food, and what items we should avoid eating. Although this makes intuitive sense, proving this in humans would be impossible—children would have to be raised in a world without certain smells for their whole lives to demonstrate the what smells are hardwired. With rodents, however, preventing certain aromas or foods from entering their environment for the entirety of their lives doesn’t present many technical difficulties. Better understanding something as how rats experience the smell of almonds may give new insight into how our brains work. While much work remains to confirm this theory, the current results are nothing to sniff at.
Ferris, C. F., P. Kulkarni, et al. (2005). "Pup Suckling Is More Rewarding Than Cocaine: Evidence from Functional Magnetic Resonance Imaging and Three-Dimensional Computational Analysis." The Journal of Neuroscience 25(1): 149-156.
Kulkarni, P., T. Stolberg, et al. (2012). "Imaging evolutionarily conserved neural networks: preferential activation of the olfactory system by food-related odor." Behav Brain Res 230(1): 201-207.
Fired by the virus, hired by the host: Off-target HIV-1 drug still get’s the job done!
By: Debra Ann Ragland
Just as at its onset of its discovery in 1981, the race to finding a cure for HIV-1 has not lost momentum. With headlines buzzing about the one man cured of HIV-1, the general public has become increasingly hopeful that the epidemic will soon cease. However, drug resistance, the reduction in a particular target’s vulnerability to a drug, has become the most substantial issue concerning HIV-1 therapeutic administration. Drug resistance in HIV-1 primarily arises when patients taking highly active anti-retroviral therapy (HAART) do not adhere to their drug regimens as prescribed, most likely due to the high pill burden or the side effects of the drugs. HAART, composed of five classes of inhibitors, target proteins needed for the virus to reproduce. If a patient doesn’t comply with HAART therapy the virus becomes resistant. A subset of virus survives, which circulate in the patient at low levels until the major population declines due to prolonged drug treatment. The new populations vary from the original virus and the drugs no longer inhibit them.
Recently, scientists in the group led by Maureen M. Goodnew found that nelfinavir, one of the drugs used in HAART therapy, still inhibits other aspects of HIV-1 infection even though it no longer inhibits the original target in HIV-1. According to Maureen’s group nelfinavir alternatively reduced chronic inflammation caused by HIV-1. Chronic inflammation, an attempt by our immune systems to begin the healing process after injury or illness, develops when antigens, foreign particles to our immune systems, persist. In a person living with HIV-1, the longer virus remains active, the longer inflammation continues. The irony of inflammation; wounds would never heal if it did not occur, but just as with most things, too much of a good thing can be bad for you. If the body cannot control inflammation and it continues into overdrive, detrimental effects on our bodies can occur, such as tissue damage, and many types of cancer.
Many scientists, including the Maureen’s group, site a process by which bacteria escape from where they normally reside in our guts, as the reason for chronic inflammation in persons infected with HIV-1. HIV-1 depletes CD4+ T-cells, the cells used to spread the message that an invader lurks in our immune systems. This depletion may break down the barrier used to keep residential bacteria restricted to the lining of our guts. Once this barrier becomes degraded, the bacteria, freed from their leashes, can travel around our bodies. Macrophages, the bacteria-hunting cells in our bodies, sense the substance coating the bacteria. When a macrophage senses something like the coat of a bacterium, it produces signals to alert the rest of the immune system that an invasion has occurred. This signaling stops in healthy individuals after macrophages have removed the antigen. And eventually inflammation subsides. On the other hand, the macrophage signaling never ceases in individuals infected with HIV-1. These patients’ immune system stays alert in a constant pro-inflammatory state. In other words, the immune system of an HIV-1 remains in overdrive.
Nelfinavir, reduces this inflammation response by jamming the macrophage protein recycling machine. With this machine blocked, the cell cannot recycle its misfolded proteins. The accumulation of misfolded proteins triggers the turning off of the signals designed to create the “kill the invader” response by our immune systems. Nelfinavir blocking the machine thus, does not directly inhibit inflammation; the steps that occur after the interaction of the antiviral drug and the proteasome cause the reduction in inflammation.
Maureen’s group found that nelfinavir treatment acts to reduce release of signals sent by macrophages known as cytokines. The group found a protein that turns on in response to the nelfinavir’s hindrance interaction. Once on, it turns off proteins known to trigger the “pro-inflammatory response” or the response by the immune system after the “danger” signals become relayed. Through further efforts by the group they showed that nelfinavir’s interference with the macrophages recycling truly begins the reduction in inflammation caused by macrophages. This allowed the group to provide evidence that nelfinavir works even though it has missed its original mark.
With all the time and effort that goes into drug design, the affirmation of first generation of HIV-1 treatment needing not to retire seems promising. Nelfinavir blocking cell recycling may happen hapharzardly or it may do this with purpose. In either case, this finding may provide a platform for old inhibitors to serve as supplements for patients to keep inflammation under control while more effective anti-retroviral therapies are administered to target the actual virus. One of many HIV-1 drugs that patients mount resistance to, nelfinavir’s method for reducing inflammation may lead to identification of other signaling pathways blocked possibly by other HIV-1 therapeutics.
Wallet, MA et al. The HIV-1 protease inhibitor nelfinavir activates PP2 and inhibits MAPK signaling in macrophages: a pathway to reduce inflammation. Journal of Leukocyte Biology. Volume 92. Pp 1-11. July 2012.
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