Communicating Science Course 2012 Blogs 


Cuckoos in Disguise: Sporting different looks to infiltrate host nests

By: Harleen Saini

Imagine this: A homeless mother in a nurse’s disguise sneaks into the maternity ward of a hospital, and cleverly replaces someone else’s baby with her own child and runs away. The unsuspecting parents take the homeless mother’s child to be their own and lovingly raise it to adulthood. An incident like this, if discovered, is bound to enrage people and possibly make headlines in the local news. While for humans, the actions of the homeless mother are clearly wrong and will be shunned by the society at large, for the cuckoo bird, this is the only way to survive.

Have you ever seen a cuckoo’s nest? Probably not! It is not because their nests are difficult to find; it is because they don’t have any nests. Most species of the cuckoo bird are ‘brood parasites’: they do not build their own nests, instead, they slyly lay their eggs in a smaller bird’s nest and leave their young to be raised by foster parents. As soon as a cuckoo hatches from its egg - blind, naked (featherless), and hungry – it has but one aim: to toss its foster siblings out of the nest and be an only chick to its foster parents. The life of a cuckoo chick thus begins with murder and is followed by deceit as they cheat their foster parents into thinking they are their own. This cycle of murder and deceit by the cuckoo has been going on for centuries (Aristotle documented this parasitic behavior of the cuckoo in his book, “The History of Animals” in 350 B.C.E.).

How has the cuckoo survived for so long without ever building a nest? It turns out that cuckoos have many tricks up their sleeve to infiltrate other birds’ nests without being caught. One of these tricks is to look like a larger bird of prey. For instance, the plumage of the common European cuckoo, Cuculus canorus, can either be gray or reddish-brown, quite like that of a hawk or a falcon. When other birds see a cuckoo, they think it’s a dangerous bird and stay clear of it. This provides the perfect opportunity for a cuckoo to find a suitable nest and quickly lay its egg. But if the goal of a cuckoo is to look scary, why look like two different dangerous birds (falcon-like and hawk-like) and why not perfect one disguise? This was the question on the minds of two researchers from the University of Cambrige, Dr. Rose Thorogood and Dr. Nicholas Davies, as they set out to study the cuckoo’s deceptive tactics and how they evolved.

In an article published recently in the journal, Science, Thorogood and Davies found out that the cuckoo’s dual disguise evolved to combat the defense tactic of its common avian host, the reed warbler. Even though cuckoos rank high on the list of successful mimics, the reed warblers soon learn to see through their disguise and attack them (scientists call this ‘mobbing’). The reed warblers also excel at social learning: if they watch fellow warblers attacking a cuckoo that looks like a hawk, it emboldens them and the attacks on hawk-like cuckoos quickly increase in frequency. One can then imagine that a high population of hawk-like cuckoos will likely increase the probability of their being recognized by the reed warblers and thereby result in a more robust defense against cuckoos. But at the same time, if the cuckoo can exist in an alternative less common form, a falcon-like form in this case, they might evade the reed warblers’ watchful eye and successfully plant their eggs in the warbler nests.

The authors tested this idea by artificially increasing the local population of one type of cuckoo. They placed wood models of either the hawk-like or falcon-like cuckoos in a small region and observed an increase in the reed warbler mobbing response to the more prevalent cuckoo type. For instance, if the hawk-like cuckoo was more commonly seen and attacked by the reed warblers in a region, the frequency of mobbing attacks on the hawk-like cuckoo by neighboring reed warblers increased rapidly. The reed warblers are therefore capable of defending their nests from the cuckoo by social learning. While the more prevalent cuckoo type (the hawk-like cuckoo in the example above) suffers from this defense mechanism, the less common cuckoo type remains largely unnoticed and sneaks its way into the reed warbler nests.

What will the reed warblers do next? Will they evolve an even more complicated defense mechanism? Will the warblers somehow learn to recognize both disguises of the cuckoo? Will the cuckoo learn to mimic more birds and develop more disguises? Or perhaps the reed warblers will simply learn to recognize cuckoo eggs, nip them in the bud, and force the cuckoos to make their own nests!

This blog is in reference to the article:
“Cuckoos combat socially transmitted defenses of Reed Warbler hosts with a plumage polymorphism” by Thorogood, R and NB Davies, NB (August 2012) Science.

For more on the life of a cuckoo, here’s an intriguing video by David Attenborough on BBC:



One if by land, two if by sea, three if by…skin? Our bacterial brethren help us respond to invading microorganisms.

By: Jacob Schrum

When someone mentions the word “bacteria”, what is the first thing that comes to mind? Do you immediately think of horrible diseases like tuberculosis or the plague? Do you imagine raw chicken swarming with Salmonella or unwashed vegetables chock-full of E. coli? Disease-causing bacteria get plenty of media coverage, but we often fail to consider how much we depend on bacteria. Our bodies contain more bacterial cells than human cells, and these live-in, non-disease-causing bacteria, also known as commensal bacteria, perform many essential roles. A new study published by Shruti Naik and colleagues in the journal Science (1) delves into one of these positive roles: commensal bacteria found on skin help our immune system fight off disease-causing microorganisms called pathogens.

To explore this role of skin commensal bacteria, Naik and colleagues raised laboratory mice in either specific pathogen-free (SPF) or germ-free (GF) conditions. The SPF mice had normal commensal bacteria but no pathogens, while the GF mice had no commensal bacteria or other microorganisms of any kind. When the scientists examined a category of immune system cells called T cells from the skin of these mice, they observed that the T cells from the SPF mice produced more of a specific class of molecules called pro-inflammatory cytokines than T cells from the GF mice. These molecules, appropriately enough, stimulate other immune cells to become more aggressive at attacking foreign invaders and cause the body-wide changes such as fever and malaise that we associate with infections. However, when they gave the GF mice the skin commensal bacterium Staphylococcus epidermidis and then examined the mice’s T cells, the cells produces the same quantity of pro-inflammatory cytokines as the SPF mice.

At this point, you may be asking yourself, “So what? If there are no disease-causing organisms present, why does it matter that the immune system needs the commensal bacteria to produce these molecules?” As it turns out, the immune system needs exposure to commensal bacteria to produce pro-inflammatory cytokines even during an infection by a pathogen. To demonstrate this, the researchers infected both SPF and GF mice with Leishmania major, a pathogen that causes skin infections. The GF mice had less swelling and tissue death at the site of infection, and the T cells from their skin produced lower amounts of cytokines. However, if the researchers added S. epidermidis at the same time they infected the GF mice with L. major, the mice had the same immune responses as the SPF mice.

At first glance, the GF mice may appear to have the advantage. The multibillion-dollar anti-inflammatory drug industry exists for a reason. Not many people want to suffer through a large inflammatory response. Nevertheless, the inflammatory response itself also exists for a reason. The infected GF mice had over 100 times as many L. major parasites as the infected SPF mice! Failure of the inflammatory response to slow down pathogenic invasions can have disastrous consequences. The bacterium responsible for the plague and the infamous Black Death during the Middle Ages killed so many people so efficiently because of its ability to slip by the body’s immune sentinels. In these experiments, however, the bacteria were on our side (well, the mice’s side, but you get the idea).

Commensal bacteria do not just play an essential supporting role at the skin; they also fulfill this task deep in the trenches of our guts. The scientific community has known for years that a healthy commensal community in our digestive tracts helps keep the pathogens at bay. When this community is wiped out—for example, by taking a lot of antibiotics—pathogens can take up residence in this prime, newly vacated real estate. The bacterium Clostridium difficile, scourge of hospitals everywhere, kills large numbers of patients by this exact mechanism.

Ever since the discovery of penicillin, antibiotics have demonstrated time and again their penchant for killing bacteria (unless the bacteria develop resistance—another huge problem I won’t mention here), but therein lies the rub: they kill friend and foe indiscriminately. We already use antibiotics at an alarmingly high rate, sometimes appropriately and sometimes not. Additionally, we feel the need to banish bacteria from all parts of our daily lives. Take a trip to any department store or large retailer and you’ll almost certainly find dozens of antibacterial products, from soaps to socks. As scientists continue to unravel the mysteries of our personal microbial menageries, maybe we can discover new, better-targeted ways to fight disease and promote health that takes advantage of the benefits brought to us by our bacterial brethren.

1. S. Naik et al., Compartmentalized Control of Skin Immunity by Resident Commensals, Science (2012), doi:10.1126/science.1225152.

Was that you or me? Pronoun confusions within the brains of autistic individuals.

By: Muazzez Elif Sikoglu

Autism refers to a complex group of brain development disorders associated with abnormalities in social interaction and communication. Autism’s effects on patients’ lives may manifest themselves in various degrees from complete lack of communication with others, as in low-functioning autism, to individuals with high IQs but abnormal social interactions, as in high-functioning autism. Have you interacted with someone who has high-functioning autism? They often have one or two amazing skills, but they may have eccentric manners. For example, friends have named Satoshi Tajiri “Dr. Bug” due to his autistic fixation with these creatures. However, based on his interest in bugs, he created the Pokémon phenomenon, one of the most popular video game franchises in the world. Similarly, Jeff Hudale, featured in an NPR piece earlier this year, has an unusual talent with numbers, but he has great hardship with literature or personal interactions. Clearly, something is different about the brains of these individuals with autism, but what is it?

For researchers, brain is still somewhat of a black box: it receives stimulations from the environment and then dictates actions, but we still don’t understand much of the processing that occurs in between. Scientists have been pursuing various methodologies to investigate the brain. Magnetic Resonance Imaging (MRI) has been used to visualize internal organ structure since the early 1970s. In the early 1990s, Seiji Ogawa and colleagues discovered a way to image the “brain-at-work”. In simple terms, the brain uses oxygen while working, so functional MRI (fMRI) utilizes the changes in oxygenation level of the blood to show the regions of the brain employed whilst performing a certain task. Scientists began to apply fMRI technology to autism research in late 1990s, when the National Institutes of Health showed a significant interest in this area. Although many studies have been published in this field since then, the complex nature of autism means there is still a lot to discover and hence a long way to a cure.

Recently, a study by Akiko Mizuno and colleagues from Carnegie Mellon University examined the way that individuals with high-functioning autism handle the process called “deictic shifting”. Deictic shifting refers to the re-mapping of personal pronouns such as “I” and “you” between the speaker and the listener during a conversation. For example, when Speaker 1 asks Speaker 2, “How are you today?” Speaker 2 might reply, “I’m well, thanks. How are you?” In this conversation, each speaker successfully re-mapped “you” so that it had the meaning “the other person in the conversation”. This study used fMRI to measure autistic and healthy participants’ brain activity whilst lying in the noisy tube of a MRI system and performing a task addressing the ability to re-map the pronouns: The task included a sequence of two scenes. In the first scene, a woman named Sarah held a picture of two objects (a vegetable and a building). In the second scene, Sarah held the same picture, but it was folded in half so the participant could only see one of the objects while Sarah saw only the other object. In this second scene, Sarah asked a question such as ‘What can you see now?’ or ‘What can John see now?’ or ‘What can I see now?’ or ‘What can Sarah see now?’ where John was the name of the study participant. The screen then displayed two questions and the participant indicated his/her choice by a button press. These questions tested the participants’ ability to address self or the other person via “shift” or “fixed” conditions. For example, the question “What can I see now?” evaluated the participant’s deictic shifting ability because the participant had to comprehend that the personal pronoun “I” referred to Sarah. Third-person questions, like “What can John see now?” represented “fixed” conditions because they required no shift.

The findings were striking. First, the individuals with autism took longer to respond to both types of questions -especially the “shift” questions- and they gave less accurate responses than the healthy control participants. Second, fMRI findings revealed diminished communication between two important brain regions: the anterior insula, a brain region positioned in the front of the brain and involved in functions including perception, self-awareness and self-consciousness; and the precuneus, located at the back of the brain and involved in spatial information processing. The reduction in connections between these remote, yet functionally related, regions of the brain occurred when the task required deictic shifting. Interestingly, when the task did not require deictic shifting, such as the “fixed” conditions, the underconnectivity for individuals with autism was not observed.

What does all this mean? In a typical brain, there exists a synchrony between the brain activity of different regions and this synchrony presents itself through strong connections. Individuals with autism have a disruption of this synchrony, leading to various problems affecting their daily lives. As in the case of this study, they may have difficulties shifting between the pronouns, which can make relationships with others more challenging.

Due to its complexity, treatment of autism spectrum disorders has a long way to go. However, studies such as this one using the state-of-art brain imaging tools will allow us to better understand the dysfunctions underlying the disorder and hopefully lead the way to at least some behavioral therapy methods.

Mizuno A, Liu Y, Williams DL, Keller TA, Minshew NJ, Just MA. The neural basis of deictic shifting in linguistic perspective-taking in high-functioning autism. Brain 2011;134(Pt 8):2422-35.

Hope for malaria eradication: another way to fight

By: InYoung Song

When you plan to travel to humid tropical areas such as sub-Saharan Africa and Amazons, you should take prophylactic medicine for a disease for about a month, starting from 1~2 weeks before a trip. What a nuisance! Why should you take it? That’s because there is no vaccine for the disease. A class of mosquito-transmitted bacteria, Plasmodia, causes one of these deadly diseases, malaria. People infected with the bacteria show a cycle of symptoms, from shivering to fever to sweating [1]. Annually 500 million people contract malaria and 1 million die from it [3]. Unfortunately, in 2010, almost 86% of malaria deaths came from African children under the age of five [2]. Plasmodia have evolved clever ways to evade our body’s defenses making vaccine development difficult. These bacteria first grow in liver cells (hidden from our immune system). There they change shape while multiplying with 60 different kinds of surface proteins. In the end, they weaken our immune system. Like other pathogens, Plasmodia often show drug resistance and survive treatment [5]. Needless to say, we should devote more resources to developing efficient vaccines and resistance-free drugs for malaria treatment.

A recent news report brought new hope for malaria treatment [5]. The report introduced an innovative strategy that might pave the way for development of new promising therapeutics for malaria. Traditional treatment methods attempted to kill malaria-causing bacteria directly with chemical drugs. Butler et al. presented a new approach, focusing on using the body’s own immune system to fight Plasmodia [6].

Our immune system functions like a double-edged sword. It defeats any possible invaders using very powerful weapons: a variety of immune cells and other small proteins. Though integral to our body’s defense, these powerful weapons can severely damage our own tissues when over-stimulated by a large amount of invaders or by a long-term attack. To prevent such detrimental side effects, our immune system devised a self-protective method. Our most important immunologic weapons, T cells (thymus derived immune cells), lose their abilities to help other immune cells or to kill our damaged or infected cells when chronically stimulated [4]. We call these dysfunctional T cells “exhausted T cells” and this inactive state of T cells as “T cell exhaustion” [4]. In other words, too much stimulation causes these T cells to stop responding. These exhausted T cells usually express molecules on their cell surface so they remain inactive [4]. These molecules can act as messengers for T cell exhaustion, interacting with other cells of the immune system to affect the body’s response to Plasmodia.

According to the work of Butler et al., during malaria infection, T cells that should fight against Plasmodia stayed inactive in an ‘exhausted’ state. They found that exhausted CD4+ T cells, a subset of T cell populations, in the presence of Plasmodia have more messenger “receiving” molecules (PD-1 and LAG-3) on their surfaces. These signals worked together to interact with other molecules on another type of important immune cells, antigen presenting cells (APCs). When the authors blocked the signal receivers (PD-1 and LAG-3), Plasmodia immediately stopped growing and disappeared in the infected mice. In blocking these signal receivers, Butler saw an increased number of Plasmodia-recognizing CD4+ T cells as well as increased presence of Plasmodia-fighting immune molecules called cytokines. Butler’s approach seemingly boosted the exhausted immune cells, allowing them to become active again and fight against malaria infection. Their approach differed from the traditional malaria treatment methods by boosting the body’s own immune system, instead of introducing chemicals.

To link the above findings in mice to human malaria, Butler et al. compared the amounts of PD-1 in CD4+ T cells before and after malaria infection in infected children in Mali. They found that their CD4+ T cells have more signal receivers (PD-1) after infection. These findings suggested that blocking T cell exhaustion signaling in human malaria may lead to a promising treatment to eradicate malaria.

The report stressed, however, we must overcome several hurdles to using this approach for malaria therapeutics. Many signal receiving molecules besides PD-1 and LAG-3 exist, so we need to figure out which combination of blocked receivers gives specific and synergistic effects on reviving exhausted T cells. Since these signal receivers also transmit a message that our T cells should not attack our own cells and tissues, we must take caution when we block these signal receivers; otherwise, the blockade will cause self-attacking autoimmune diseases.

Developing diverse therapeutics to malaria opens up the possibility of the complete eradication of malaria through treatment, similar to our history with smallpox. I hope the efforts of Butler et al. will lead to a new therapeutic. This new therapeutic approach may give future generations of children protection against malaria-induced death and relieve the troublesome burden of travel to humid tropical regions of the world.

**** I wrote this blog mainly based on the news reports [5] listed in reference
3. Curr Pharm Des.2012;18(24):3490-504.The apicoplast: a key target to cure malaria. Macrae JI, Maréchal E, Biot C, Botté CY.
4. Nat Immunol. 2011 Jun;12(6):492-9. T cell exhaustion. Wherry EJ.
5. Nat. Immunol. 2012 Feb; 13(2): 113-115. A new therapeutic strategy for malaria: targeting T cell exhaustion. Freeman GJ, Sharpe AH.
6. Nat. Immunol. 2012 Feb; 13(2): 188-195. Therapeutic blockade of PD-L1 and Lag-3 rapidly clears established blood-stage Plasmodium infection. Butler NS, Moebius J, Pewe LL, Traore B, Doumbo OK, Tygrett LT, Waldschmidt TJ, Crompton PD and Harty JT.

RE-RE-RE-peated Mistakes In Your DNA Can Cause Fatal Diseases

By: Gabriela Toro

The different genes in our bodies dictate eye color, hair, height, and other traits we inherit from our parents. The human genome contains thousands of different genes, and a large portion of these genes serve as blueprints for protein production in our bodies. Genes are made up of DNA, which is a double helix-shaped molecule that looks like a twisted ladder or a piece of Hershey’s Twizzler candy. Four smaller fragments collectively termed “nucleotides”, (A, G, C, and T for short), are the building blocks of DNA. They can be thought of as the letters of the genome alphabet that come together to form all of the different genes we possess. Like words, every gene has a specific sequence of these letters and every three letters in any given DNA sequence acts like a barcode for a particular product. Hence, the products of the various three-letter code combinations form the basic units of proteins. Therefore, the DNA sequence will dictate what protein gets produced in the body. In order for the cells in our bodies to begin producing the protein that corresponds to a particular gene, it must first pass GO like in Monopoly. The three-letter combination “ATG”, encodes the start site for the cell’s machinery to make a protein. Similarly when the machinery must come to a stop another 3-letter combination will terminate it.

After researchers cracked the human genome sequence Sherlock Holmes style, they found that seriously fatal diseases like Huntington’s, Myotonic dystrophy, and Fragile X syndrome are caused by changes in the DNA sequences of affected individuals.

Researchers discovered that there is a particular error caused by a series of 3 letters that just keep repeating, and repeating, and repeating in the genome. These repeats are called expansions, and they affect the overall sequence of DNA resulting in the production of too much protein, too little protein, or no protein at all.

The most common disease, Huntington’s, affects the neuronal cells in the brain causing deterioration. Scientists revealed that people with this disease contain 36 to 120 repetitions compared to a normal person with only 10 to 28 repeats. The biggest concern for doctors is that it is hereditary; this means that if your father has this disease you have a 50% chance of developing the disease as well.

Furthermore, recent studies show that genes containing 3 letter repeat sequences with mistakes cause the cell to begin producing a protein without first passing GO, resulting in an accumulation of faulty proteins. Scientists do not know where the GO signal is located for these repeats, and during various tests, protein production started at various different places, resulting in many proteins with different lengths. This leaves scientists trying to address the following questions: Does the specific number of repeats present in each genome cause a specific disease? Can 4,5 or 6 letter repeats also cause diseases?

In addition to repeats in a DNA sequence, specific groupings of repeated proteins can also cause disease. The Creutzfeldt-Jacob disease is caused by the twenty-four-fold repetition of an eight-protein combination known as an “octapeptide”. According to researchers, people with mutations can have up to nine extra octapeptides. Patients with four extra octapeptides observe the symptoms of the disease at an average age of sixty. When patients contain five to nine extra octapeptides, the average age of onset is thirty to forty years. When these faulty multi-proteins are formed during disease, the proteins clump together in different tissues of the body. Studies in mice and humans show that these clumps are toxic to cells and that they may cause destruction of neurons leading to symptoms seen in Huntington’s and other neurodegenerative disorders.

Finally, new research indicates that viruses can start protein synthesis without the GO signal. This may explain how these repeats code themselves. Future endeavors include understanding how the virus mechanism works so we use it in our favor. In conclusion, sequencing of the human genome gave scientists many clues to solve the mysteries of various diseases, yet multiple aspects are still puzzling. This new finding opens the doors to many research opportunities regarding diseases caused by repeat expansions.

1. Pearson CE. Repeat associated non-ATG translation initiation: One DNA, two transcripts, seven reading frames, potentially nine toxic entities! PLoS Genet. 2011 Mar;7(3):e1002018.

If You're Watching Your Weight, Then Choose Your Friends Carefully

By: Markus Vallaster

Have you ever wondered why you are gaining weight, even though you haven’t made any particular changes in your diet? Well, part of the reason why we gain weight might be because of obese friends. Sound absurd? Then consider this: a team of researchers from Harvard Medical School in Boston analysed data from the Framingham Heart Study which show that your chances of becoming overweight increase by 57% if your friends have recently become obese themselves.

The researchers looked at data from 12,067 people who had been frequently examined over the last 30 years. Of course, not all of them are sick or obese. The original Framingham Heart Study was initiated in the New England town of Framingham and sought to investigate different causes of high blood pressure or heart attacks in a well-defined population, and now includes members of even the third generation. People were asked to come to a physical examination and to answer some written questions on a regular basis every 3 years. There was a very low dropout rate, mostly due to the death of participants. Between 1971 and 2003, there were seven appointments, where participants saw either a doctor or a nurse. Serendipitously, the staff who performed these examinations also documented all sorts of other information such as their relationships.

All what Nickolas Christakis and James Fowler, the authors of the recent study published in the New England Journal of Medicine, had to do was feed a computer programme with the social data and create networks of how people are connected and linked to each other. These connections were classified in 6 groups depending on how loose or tight and how close or far away those relationships were. The direction of friendship also played a role, i.e. does the examined person identify somebody else as a friend, or is it the other person who identifies the examined person as a friend, or is the friendship mutual (both parties claim to be friends). These analyses led to the observation that you are more likely to be obese if your friends are obese too. While it also turned out that you are more likely to become obese if your sibling gains weight, the impact is less than if your best friend is obese, which increases your risk of obesity by 57%. The effects are even stronger if your best buddy is of the same sex. Interestingly, the opposite sex does not have such strong an effect on you, which is also true for married couples.

The study suggests three ways that your friends and family can influence your weight. First, you choose your friends because they are “like you”. For example, sporty people tend to hang out with other sporty people, and similarly obese people prefer to hang out with other overweight people. Second, you both experience the same things in your lives. Third, your friends really have an effect on you and your weight, i.e. when they suddenly gain weight (even though they were not obese before) you start doing the same thing. Through a lot of bioinformatics and statistical analyses, the researchers could rule out possibilities one and two. There were no common confounding factors, and also changes in the environment did not play a role at all.

This leaves us with the third explanation. Is it really possible, that obesity is contagious just like the virus your daughter brings home from Kindergarten? Well, the researchers don’t say that! But behaviours of people around you affect your own life and how you see things. If your best friend suddenly gains weight, why would you condemn them? Isn’t it more likely that you adapt to some of their new life style, just as you would do if they want to join a bowling team or start horseback riding. That’s what friends do, they socialize together and share their lives. That’s the reason why in the study it didn't matter how far apart the friends lived from each other. It’s about behaviours and relationships and how you respond to them.

As with all studies, don't take them too seriously. It’s an experiment. Therefore, don't change your friends, if you really like them! But consider how you subconsciously respond to people with whom you are friends.

For further reading please see:
Christakis NA, Fowler JH. The spread of obesity in a large social network over 32 years. N. Engl. J. Med. 2007 Jul. 26;357(4):370–9.

Successful Combat of the Flu Requires Teamwork.

By: Allen Vong

Every year, elderly and young children have to take the flu vaccine to protect themselves from seasonal flu, caused by the influenza virus. The vaccine works by eliciting an antibody response to the surface proteins of the virus; like putting out a police alert on a car. But the flu virus can evolve and mutate to trick the immune system by varying its surface proteins, or in other words change the license plate or color of the car, so the immune system or police can't recognize it. The flu virus mutates so frequently that to design vaccines, scientists must guess what the predominant strain will be for that year. This time consuming process is not optimal because you must vaccinate every year, and if they guessed the wrong strain you could still get the flu!

By understanding how the immune system naturally combats the flu virus, scientists can engineer better vaccines. The immune system employs multiple arms of defenses to combat the virus. The three main arms include B cells, which secrete antibodies that bind and neutralize the virus, CD8+ T cells that directly kill the infected cell to prevent viral growth, and CD4+ T cells that coordinate the attack by secreting signals to the CD8+ T cells and B cells. All three arms also generate memory cells that will remember the flu and sit waiting until the virus appears again. Upon second exposure to the flu, these memory cells expand to a larger extent and deal with the flu virus so effectively you won't feel the symptoms. Teasing out which arm is the most important for protection or if more than one arm is required in combating the flu has proven difficult. Currently flu vaccines target the B cell response as activating this arm of defense has been thought of to be providing the best protection.

K McKinstry and colleagues have made the exciting discovery, published in the Journal of Clinical Investigation, that it's not all B cells, but memory CD4+ T cells will also protect against flu. They cooperate with both B cells and CD8+ T cells1 to build the best response against flu. They discovered this by infecting different mice with the flu. These mice lacked certain arms of the immune system. For example, some mice lacked B cells or T cells or both. Then the authors added back each arm by itself or in combination to see which combination was able to protect against the flu. CD4+ memory T cells alone cannot protect against the flu but with both CD4+ memory T cells and antibodies from B cells the mice survive the flu at a dose that would normally kill them. Importantly, this protection was much better compared to just B cells alone.

So what does this mean for vaccines and the seasonal flu? Scientists should engineer flu vaccines that promote the generation of CD4+ memory T cells. These cells protect by many mechanisms and will synergize with B cells and CD8+ T cells for protection. Even more exciting is that CD4+ T cells usually recognize parts of the virus that do not change as much; like having an alert on a car engine, which the culprit would have a harder time changing. For the virus and immune system, it means the immune system targets internal proteins, which the virus cannot change without messing up its life cycle. Since antibodies bind to the outside of the virus and the flu virus is notorious for having many variants of its outer surface, a better approach is needed. By generating vaccines that promote CD4+ memory T cell responses along with antibody production, we can provide protection from most flu strains. A good vaccine will provide long lasting protection against a broad range of flu viruses. Now with rising healthcare costs and an aging population, a good flu vaccine will be a welcome benefit.

The work by K McKinstry and colleagues show that there is much to be discovered about how your immune system combats the flu. With many flu scares recently like the swine flu and H5N1, it is clear that we must further our understanding of our body's immune defenses against influenza virus. The more we know, the better prepared we are for the next pandemic flu.

1. McKinstry, K et al. J Clin Invest. 122(8), 2847-2856 (2012) 

Virus – the unlikely hero for those with inherited hearing loss

By: Jason Yang

When you dip your head into the swimming pool, what does it sound like to hear someone speak? Words sound distorted and fuzzy. Now, imagine hearing that fuzziness or, even worse, complete silence when you see someone move his or her lips. Then, imagine being born that way and never being able to experience what anything really sounds like. For about 2 in every 1000 babies born, this is what they will hear for the rest of their lives.

Traditional methods for helping these patients include hearing aids and implants. However, half of the patients have genetics defects that result in hearing loss. Since these devices only work to make the sounds louder or easier to hear, they do not help as much for patients with genetic defects in hearing. Recently, however, scientists from University of California San Francisco, University of Pittsburgh, and The Ohio State University successfully restored hearing for mice with inherited hearing loss due to genetic defects. Even more exciting is the fact that they did this with the help of a virus.

Before talking about how a virus can ever be beneficial, let me back up and explain what a genetic defect means. During development, our ears require different cells to help them grow. These cells function like factories, manufacturing various components that will help the ear receive sounds from the outside and turn them into information for our brain on the inside. In order to manufacture the components, our cellular factories must have orders that tell them how to build each component. Those orders are our DNA sequences, and each part of the sequence directs the cell to manufacture a specific component. Sometimes, a mistake occurs in the order, and we call this a genetic defect in the DNA sequence. As you can imagine, an order with a mistake results in the wrong or non-functioning component being made. When patients have these genetic mutations that result in defective components for the ear, they may not perceive sound the same way that a normal person does.

So how does a virus help with hearing loss? Since some hearing loss come from mistakes in the DNA sequences, scientists wanted to deliver the correct sequence. In other words, the scientists aimed at delivering the correct orders to the right factories so the factories can produce functioning and correct components that will help the ears naturally perceive sound. In this case, the virus is the deliveryman.

Viruses normally attack our bodies by attaching to our own cells, injecting their own DNA sequences, and hijacking our cellular factories to make components that are beneficial for the viruses but harmful for us. The scientists used a type of virus called adeno-associated virus, and they modified it so that the virus only produced the components desired by the scientists. Using this delivery system, the scientists focused on a gene necessary for hearing called VGLUT3. When VGLUT3 is defective, the patient loses hearing because the genetic defect in the gene makes a non-functioning component, which is called the VGLUT3 component.

The VGLUT3 component helps relay the sound information to our brains. Mice with a mutation in the VGLUT3 gene are deaf from birth. In this study, the scientists put the correct VGLUT3 gene in the virus and injected the modified viruses into the ears of deaf mice. They wanted to see if the deliveryman would arrive at the right factory with the right order so the correct component gets produced.

The scientists found some surprising results. First, the virus targeted only the cells that play a role in the development of the ear. This is important because if the viruses delivered the genes to other cells, then side effects might occur. Just as you never want a deliveryman to deliver your package or order to another place, the scientists made sure that the virus delivered to the correct set of cells. Second, the delivery of the correct gene produced measurable hearing recovery for at least two weeks. However, while the measured responses resembled the normal hearing mice, the virus-treated mice still differed in the actual natural hearing experience from normal mice. Third, the hearing recovery lasts at best for seven weeks. Many of the tested mice start to lose hearing again after that period of time.

The scientists concluded that the adeno-associated virus successfully delivered the correct gene to the cells that help develop hearing in ears. Nonetheless, this is not a silver bullet. The scientists proposed that more studies would reveal various changes that could improve the hearing recovery duration. The caveat is that the authors only focused on one genetic defect, the VGLUT3 mutation. Many different mutations exist that cause inherited hearing loss. Therefore, future studies should focus on other mutations so people with different genetic mutations can benefit from this strategy. This study opens the door for further experiments based on genetic information delivery. While it may take years or even decades before fruition, this study is a promising first step towards a better treatment.

Let’s go back and imagine again that you are in the pool and underwater. Hearing the fuzzy words of your friend’s voice, you rise up from the water. Suddenly, those words become crisp and clear, like raindrops beating against a windowpane or an apple being sliced by a razor sharp knife. Someday, a child with inherited hearing loss, after years of hearing fuzziness and silence, may hear that same crisp clear sound that you hear. Can you picture that?

And, can you imagine that this is all possible because of a virus?

Akil, Omar. Et. al. “Restoration of Hearing in the VGLUT3 Knockout Mouse Using Virally Mediated Gene Therapy.” Neuron. Cell Press. July, 2012.

Visible Miracle

By: Ozge Yildiz

Can you describe a place you have never seen? How many times can you dream about how it looks like? These questions may make us think how people suffering from Leber congenital amaurosis feel.

Leber congenital amaruosis (LCA) is an inherited early onset childhood blindness occurring with an incidence of 1 in 30,000 births worldwide. In the first few months of age, the person carrying mutations in the gene responsible for this disease loses his vision permanently. Fortunately, science paved the way to cure such people using gene therapy.

The retina is the only light sensitive tissue in the human body. After the light impulse hits the retina, the chemical and electrical cascades are interpreted in the brain as an image. The ability to see necessitates fully functional light sensitive cells in the retina, namely photoreceptors. Rod and cone photoreceptors constitute the inner most layer of the retina. The development of these specialized sensory neurons directly affects visual perception. Retinal degeneration stems from either defects in the development of retinal cell layers or defective gene products required for vision. Mutations in several genes such as Cep290, Rpe65 and RPGRIP1 have been identified to cause LCA. However, only the case caused by mutations in the gene Rpe65 was treated by gene therapy.

Rpe65 is expressed in retinal pigment epithelium (RPE), which supplies nutrients to photoreceptors. Rpe65 is critical for the visual cycle because it helps synthesize 11-cis retinal, a Vitamin A derivative. Photoreceptive pigments namely opsin and rhodopsin capture light with the help of 11-cis retinal. Mutations in Rpe65 impairs the production of 11-cis retinal, which results in defective rhodopsin turnover. Thus, a visual image cannot be perceived.

Studies done with mice, dogs and humans revealed that the mutations in Rpe65 lead to disorganized photoreceptor structures, thinning of retinal cell layers and reduced levels of opsin. In the last decade, for the sake of finding a treatment to blindness, therapeutic gene delivery gained remarkable attention. Several types of viral vectors have been developed and administered to the disease models. One of these, adeno-associated virus (AAV) has come forward in research due to its safety and efficiency in targeting the desired tissue. Dejneka et al. showed that delivery of human Rpe65 to retinal pigment epithelium in a mouse model of congenital blinding disease restores the visual deficit.

They introduced the AAV containing human Rpe65 into fetal and young adult mice. Following the subretinal delivery of the virus into fetuses, they evaluated the RPE65 protein levels post-treatment. As expected, detectable levels of RPE65 protein were seen only in treated eyes and not in untreated eyes. The course of the eye development in the treated eyes was normal after injections. This showed that photoreceptor degeneration was corrected by RPE65.

Electroretinography (ERG) is used to evaluate retina function. ERG measures the electrical output from the corneal surface of the mouse eye. In utero injected and uninjected eyes were subject to ERG analysis. ERG readouts appeared nearly normal in Rpe65-injected eyes. Photoresponse sensitivity was gained back after gene delivery.

Although the retina appeared normal, the authors still questioned whether perception of light occurred. Phototransduction is a consequence of a highly active and continuous process that includes continuous turnover of rhodopsin. To fully answer whether rescue of vision by gene delivery occurred, they checked the ability of photoreceptors to generate rhodopsin. They harvested retinas from the animals injected in utero, uninjected animals, control animals injected in utero (basically a salt solution), and animals injected as adults. From these retinas, Dejneka et al. extracted the visual pigment rhodopsin to measure its content. They detected significant levels of rhodopsin in both mice treated as fetal and adult. In comparison, they could not detect any rhodopsin in uninjected or control-injected eyes.

This study emphasizes the possibility to treat a congenital blinding disease prenatally. Also, in utero gene delivery can compensate for any developmental abnormalities after birth. During the past decade, the research on therapeutic gene delivery for RPE65 jumped into clinical trials and ended with administration into adult patients. However, the lack of fully normal ERG results in treated LCA patients prevents the gene therapy from progressing further. Nowadays, virus re-administration studies aim to replenish sufficient levels of RPE65 in the retina.

RPE65 is the first gene that ended with a potential retinal gene therapy for Leber congenital amaruosis. Human clinical trials promise to match the levels of success attained in animals models for the near future.

N. S. Dejneka, E. M. Surace, T. S. Aleman, A. V. Cideciyan, A. Lyubarsky, A. Savchenko, T.M. Redmond, W. Tang, Z.Wei, T. S. Rex, E. Glover, A.M. Maguire, E. N. Pugh Jr., S. G. Jacobson, J. Bennett, In utero gene therapy rescues vision in a murine model of congenital blindness. Mol. Ther. 9, 182–188 (2004).


Beetle feet: how to stay dry underwater

By: Matija Zelic

How many times have you seen an insect walking straight up a vertical wall or even upside-down on the ceiling? Seeing a beetle clinging to and moving about the underside of a leaf is as second-nature to us as the actual feat is to a beetle. Maybe we don’t know how the beetles do it but it’s not as exciting as a magic trick. However, what if these beetles could actually walk underwater? Now that’d be a magic trick we’d be more interested in seeing. Indeed, as shown by Drs. Hosoda and Gorb, the green dock leaf beetle can perform the trick with ease, and they’ve figured out the magician’s secret; it’s all in the feet. The beetles trap air bubbles underneath their feet that enable them to move about underwater almost as well as on land.

The beetles have small setae, or hair-like structures, on the bottom of their feet. They secrete an oily liquid onto these hairs to increase the adhesive forces that allow them to attach to and walk on various surfaces, no matter the incline. Even after heavy rainfall, when the surface of the leaf is still slick, the beetles can meander about. However, people presumed that underwater adhesion isn’t possible since the water molecules would disrupt the adhesive forces of the oily hairs on the bottom of the beetle’s feet. Naoe Hosoda, a materials scientist from the National Institute for Material Science in Japan, and Stanislav Gorb from the University of Kiel in Germany used the European green dock leaf beetle as an experimental model to address whether these beetles can actually walk underwater, and how they accomplish the feat.

Going out into the wild, the scientists collected 29 beetles for their studies. They would put the beetles on a stick and have them walk into a water bath, thus creating the land to water transition that should disrupt the adhesive forces of the hairs on the beetle’s feet. Remarkably, the beetles walked off the stick right onto the smooth, clear bottom of the water bath. Using an optical microscope, Hosoda and Gorb observed white areas which suggested that air bubbles were stuck between the hairs. As the beetle walked along the underwater surface, the bubbles would move along with it, mimicking the leg movement. It seemed that underwater the trapped air bubbles were creating a dry surface for the oily hairs on the beetle’s feet similar to the adhesive properties the hairs exhibit on land. To test this the researchers added a small drop of detergent to the water, which caused the beetle to lose contact with the bottom of the water bath and float up to the surface. Additionally, the authors measured the pulling force the beetles could generate underwater as opposed to on land. They used a drop of beeswax to attach the beetles to a human hair which was connected to a force detector. No significant difference in pulling force was observed underwater when compared to the force on land. The duo concluded that the bubbles trapped between the oily hairs are able to displace the water and create a dry microenvironment that the beetle’s feet can adhere to as if they are walking on land.

Why re-invent the wheel if nature has evolved and shown us the blueprint for how to do it? Using the fine microstructure of the beetle’s feet as a guide, Naoe and Hosoda designed a synthetic polymer structure with pillars on the bottom to imitate the beetle’s tiny hairs. They placed air bubbles between the pillars and, using a force detector, measured the adhesive power of their foot-like plate compared to a smooth silicone plate. The ‘hairy’ pillars trapped the bubble in place and allowed for greater adhesion compared to the smooth plate where the bubble moved around, with nothing to hold it secure. Thus, Naoe and Hosoda proved that the arrangement of the bubbles trapped between the beetle’s oily hairs allows their feet to adhere even to underwater surfaces.

As a final homage to the beetle’s ingenuity, the researchers made tires with the pillar microstructure and put them on the bottom of a small yellow toy bulldozer. Similar to the beetle, the toy had no problem sticking to the bottom or sides of the water tank. Using the beetle’s method of trapped air bubbles as a guide, we could develop underwater adhesives to improve and stabilize underwater machines and structures. Knowing the secrets to nature’s magic tricks could prove useful in developing our own man-made shows underwater.

Gorb, S.N. & Hosoda, N. 2012. Underwater locomotion in a terrestrial beetle: combination of surface de-wetting and capillary forces. Proc Biol Sci 8 August 2012 [E-pub].


“No sacrifice, no victory”

By: Xiaohu Zhao

If you are a die-hard fan of the transformers series, then you are probably very familiar with this quote from Optimus Prime. Since the first war ever recorded in c. 2700 B.C. (1), one that was fought between Sumer and Elam, there have been 3010 major wars recorded. With each battle won, many men and women had to sacrifice their lives to achieve the necessary victories. Just like humans, insects such as termites also have similar social behaviors.

Researchers from the Institute of Organic Chemistry and Biochemistry, Academy of Science of the Czech Republic have discovered a self-sacrifice defensive mechanism used by the workers of termite subspecies Neocapritermes taracu to defend against other species of termites. There are two types of Neocapritermes workers identified by the researchers; one is called white workers and the other is called blue workers. Both white and blue workers can undergo autothysis (suicide) and burst toxic liquids killing other foreign termite species upon aggressive encounters. But blue Neocapritermes workers possess a unique pair of dark blue and elongated dorsal spots at the thorax-abdomen junction. These backpack looking blue spots are actually a pair of crystal-like structures, and a few seconds after emitting a droplet of blue fluid, the liquid becomes sticky and the blue color fades out. As stated by the authors, “these crystal structures are enclosed within pouches formed by posterior outgrowths of the metanotum over the first abdominal segment. The crystals are produced by a pair of glands located below the epidermal cell layer at the anterior part of each pouch.”(2) As Neocapritermes workers age, their mandibles gradually wear out due to use, and they can no longer renew the mandibles by molting. In the article, the authors showed that as blue workers lose their ability to feed on decayed wood, they gradually build up their suicidal backpacks to fight off other species of termites. The authors found that “mature Neocapritermes workers showed a positive correlation between fresh weight and mandible sharpness index and a negative relationship between crystal weight and mandible sharpness index.” But what are these blue colored backpacks and why are they so important to the blue Neocapritermes workers? The authors revealed the answer as following.

Blue workers have been shown to be more aggressive than white workers when they encounter other soil-feeding termites such as Labiotermes labralis. The authors performed a very interesting experiment showing that the blue crystal backpacks are essential in harming other termites after suicidal bursting. They first removed the blue crystal backpacks from blue workers and discovered that this caused a reduction in the toxicity of blue worker’s bursting fluid to L. labralis compared to white workers. However, when the blue crystal backpacks were surgically added onto white workers, the toxicity of white workers' bursting fluid was greatly enhanced.

If these blue crystal backpacks indeed play a role in increasing the toxicity of Neocapritermes workers' bursting fluid, there must be something interesting in them. The authors discovered that an important component of the blue backpack crystal is a 76-kD protein. A high amount of copper was also detected in the 76-kD protein using mass spectrometry. Considering the molecular weight of the blue crystal protein and the presence of large amount of copper, the authors suggested that the blue crystal protein is an oxygen-binding type III copper protein of the hemocyanin/phenoloxidase family which is known to occur in arthropods.

It is truly amazing that insects like Neocapritermes termites can develop such a sophisticated defensive mechanism to protect their territory against other invading termites even if it means sacrificing their own lives. Just like Optimus Prime used to say “No sacrifice, no victory.”

2. J. Šobotník1,*, T. Bourguignon2,3,*, R. Hanus1,2,†, Z. Demianová1, J. Pytelková1, M. Mareš1, P. Foltynová4, J. Preisler4, J. Cvačka1, J. Krasulová1,5, Y. Roisin2. Explosive Backpacks in Old Termite Workers. Science 27 July 2012.

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