Communicating Science Blogs 2012 

 

Exploiting the Etiology of Huntington’s Disease: A Possible Therapy for Stopping Huntington’s Disease in Its Tracks

By: Spencer Adams, Jr.

A person diagnosed with Huntington’s disease today may have been accused of being possessed by devils for their behaviors in the sixteenth century. It was not until the end of the nineteenth century that the disease was understood as a natural inheritable ailment. Luckily, the understanding of Huntington’s has progressed significantly since the days of our superstitious ancestors. However, the treatment of the disease has not progressed as well.1

Huntington’s disease is eventually fatal in all cases and no cure exists.1,2 The inherited disease is the result of an alteration in a section of a person’s DNA known as the Huntingtin gene.1,2,3 If one has Huntington’s, his or her child has a fifty percent chance of inheriting the disease.2 The hallmarks of Huntington’s include a wide array of cognitive and physical impairments, which progress at varying rates for different individuals who carry the altered gene.2 Traditionally, treatments for the disease only manage the symptoms of the disease, and not the cause of the disease.1,2 In other words, the current treatments can only slow the disease or improve quality of life while waiting for the inevitable pathology to develop. There are no remissions with Huntington’s.1

Huntington’s disease results in a progressive decline in a victim’s functions by altering the end product of the Huntingtin gene. This end product of the gene is known as a protein. To illustrate how a protein is produced from a gene, imagine a group of people handing copied notes to one another. An original “note” has a small section transcribed by a messenger, then carried to and given to a recipient. This person will translate the note into a new language. The first note would represent DNA, the next note would be what we term RNA, and the third note in the new language would be what we call protein. The process is diagrammed below:
SpencerAdamsImg

The Central Dogma of Molecular Biology
The illustration demonstrates the process of getting from DNA to protein by an RNA intermediate. If the RNA is destroyed or blocked in some way, the protein cannot be produced. (Illustration4)


It is important to note that only a section of the DNA was transcribed to produce the RNA just for one gene. This one gene produces a specific protein when translated. This process occurs routinely and is referred to as “the central dogma of molecular biology.”

If a change is made to the original gene, the transcribed RNA will reflect the change and the resulting protein will also reflect the change. This is how Huntington’s disease causes trouble. The altered gene produces toxic changes to the protein and result in the degradation of brain cells called neurons.1 A way of stopping the process of producing the altered protein would provide a way to put the brakes on Huntington’s disease and slow or stop the disease progression. If there was a way to prevent the RNA message from getting to the protein stage, the message would not result in disease and the problem would be diminished. To do this, scientists have recently employed a process that uses special RNAs engineered to attach specifically to altered Huntingtin RNAs to stop them from producing their toxic proteins.3 The work has been done in human cells thus far and has been shown to work effectively to decrease the amount of altered RNA in these cells.3

Even more interesting is that they were able to stop the altered Huntingtin RNA and not the normal Huntingtin RNA.3 Having this specificity is important, because everyone has two copies of the Huntingtin gene, one from their mother and one from their father. In Huntington’s disease, the patients typically only have one altered copy.3 The normal Huntingtin gene is beneficial for helping certain nerve cells live, so preserving the function of the normal version is important.1,3 However, targeting just the altered version provides a way of improving the treatment with less side-effects.1,3

In the study, the researchers used human cells to test their method of stopping altered Huntington protein production. A problem with the approach is that the more altered the patient’s Huntingtin gene, the less likely the approach is to work.3 However, the process is thought to be applicable to about seventy-five percent of the population with altered Huntingtin genes, as seventy-five percent of a sample of American and European patients showed only three small alterations.3 Other studies have also tested the approach of using the special RNAs in mice with varying degrees of success.1 There are challenges in the way of getting the method refined for use in humans; these challenges include improving the specificity of the special RNAs for just the altered Huntingtin RNAs and fine-tuning the way they work.1 This gives hope to a majority of cases and highlights the need for pre-clinical trials to further test the treatment.

Bibliography

1. Zhang, Y., and FriedLander, R.M. Using non-coding small RNAs to develop therapies for Huntington’s disease. Gene Ther. 2011 Dec;18(12):1139-49.
2. Huntington’s disease. A.D.A.M. Medical Encyclopedia/ PubMed Health. [30 April 2011]. Available from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001775/ [Accessed 6 August 2012].
3. Pfister, E.L., Kennington, L., Straubhaar, J., Wagh, S., Liu, W., DiFiglia, M., Landwehrmeyer, B., Vonsattel, J.P., Zamore, P.D., and Aronin, N. Five siRNAs targeting three SNPs in Huntingtin may provide therapy for three-quarters of Huntington’s disease patients. Curr. Biol. 2009 May 12; 19(9): 774-778.
4. Editor Choice: MicroRNA and Diseases of the Nervous System. Neurosurgery CNS. [15 July 2011]. Available from http://neurosurgerycns.wordpress.com/2011/07/15/editor-choice-microrna-and-diseases-of-the-nervous-system/ [Accessed 8 August 2012]. 

 

The Classic Case of Sheep in a Wolf’s clothing

By: Amena Arif

Honesty is of the essence in any good tale. So let’s start with the truth. This story has nothing to do with sheep or wolves or clothing. For those of you still sticking around to read more, the story is about cuckoos; and the evolutionary arms race. What! Didn’t Darwin write that book back in the 1800s? Why are we still talking about it? My thoughts exactly! What is a story about cuckoos and arms race doing in one of the most prestigious science magazines called (no points for imagination) ‘Science’? Just the absurdity of it made me curious enough to want to read it. “Must be something really good to have made it into Science”, I thought as I started reading the story that had me completely blown away by the end of it. As slick and tech savvy as Science has grown over the years, once in a blue moon, a story comes along, that good old sitting-under-an-apple-tree-and-coming-up-with-gravity kind of a story that reminds you of idyllic summers of your childhood, and may remind some of you why you chose to be a scientist. I aspired to become one because it meant not having to let go of my collection of beetles, fireflies and homemade herbaria when the summer ended and school started. What does all this have to do with the cuckoos? Read on…

Female cuckoos are lazy beings, but they are also wily. They stealthily replace an egg from nests of other birds with their own, so that their young are brought up by unwilling surrogate parents (hosts), mostly warblers. Needless to say, cuckoos are not too popular with avian child protection services; or the unwilling hosts who, over the course of time, have developed ways to drive them out. But Wile. E. Coyote has nothing on cuckoos. They in turn have evolved ways to overthrow the host’s hostile defense by going undercover and pretending to be a predatory bird. Let’s be real, if Vito Corleone wanted the neighborhood baker to raise Mikey, the baker wasn’t going to shut the door in his face. Though what about the cuckoos imitating predators, again? Read on…

The big question was why female cuckoos can have multiple kinds of plumage (some are gray while the others are brown)? Does it help to mimic different predators at different times? The mechanism of this multiple or, as scientists like to throw around its synonym, polymorphic mimicry was not explained by anyone previously, until Thorogood and Davies took a hint from the two institutions that shape modern society (and apparently the avian one as well) - the Bible and the suburbia.

What the cuckoo spies found was that the warblers had been attending Sunday school and were hooked to Desperate Housewives at the same time! How else would they have combined “love thy neighbor” and “be nosy” to form their defense MO? As Thorogood and Davies realized from their experiments, the warblers watch and learn from other nearby birds how to prevent the bad parent cuckoos from dropping their eggs into the warblers’ nests. If they see their neighbors attacking and driving out cuckoos, it gives them courage to do the same when their homes are under the threat of a siege. It sufficed that some warbler families recognized that the infiltrator was not a predatory bird, and the rest followed suit to attack the other cuckoos mimicking the same predator. This spells bad news for the lazy cuckoos, right? Wrong! Read on…

Around the same time, the sad ambushed cuckoos had a movie night and happened to watch Mission Impossible. As they watched Tom Cruise mimic one evil guy after the other, their sadness slowly gave way to a genius plan. Let the warblers drive out all the gray cuckoos as they want. There will be other cuckoos disguised as a different predatory bird, and charge in unchallenged, until some other warbler family recognized them and drove them out. The cycle could continue ad infinitum. Cool, huh?

Let’s take a step back to the business end of things now. The kind of mechanism of mimicry discovered by Thorogood and Davies was unprecedented until it was published in the August 3rd issue of Science, thus justifying its publication in the globally revered research magazine. But my article is as much philosophical as it is a commentary on an interesting piece of recent research. This research serves as a great reminder for everyone that nature is the best teacher. In the past few decades, there has been too much emphasis on lab work, and in more recent times, computers and bioinformatics have emerged as dominant tools to study Biology. Model organisms, lab bred stocks that have never seen the outside of a research building are being used to chart out complex and novel evolutionary phenomena that are portrayed as representative of what happens in nature. While such tools make the life and work of a Scientist much easier, they also raise a lot of questions about the quality of research, and the veracity of conclusions drawn from it. This makes the study published by Thorogood and Davies doubly important. One, it throws light on a heretofore unexplained observation, and two (and this is the more important lesson), it reminds us to go outside and just observe nature. All answers can be found there.

Reference:
Thorgood, R and Davies, NB. Cuckoos Combat Socially Transmitted Defenses of Reed Warbler Hosts with a Plumage Ploymorphism (2012). Science 337(578), 578-580. 
 

Dynein, the smart motor who knows when it’s time to get cracking

By: Aditya Bandekar

Gears, acceleration and brakes are terms we usually associate with automobiles and machines. One would think that the only time we really pray for them to work in our favor is when we are late getting to work or when we are playing the computer game ‘Need for Speed’. Not the only places where these can come in handy, as scientists at the University of California, Irvine discovered. A cell can be thought of as containing a large number of highways made up of proteins called microtubules. The cell uses these ‘roads’ to transport almost everything, from its genetic material to cell wall building blocks, to energy molecules. Two classes of motor proteins called kinesins and dyneins play the role of trucks that transport goods on these highways from one destination to another. They have ‘heads’ which they use to walk on the highways and ‘tails’ which they use to attach their cargo. Kinesins are ‘plus end’ directed, which for the most part, means that they transport cargo towards the edges of the cell. Dyneins on the other hand, transport cargo in the opposite direction, towards the interior of the cell. When delivering goods, time is of the essence, but getting the destination correct is equally important, so there are mechanisms in place to regulate the time and location of delivery by these nano machines.

We may want to do great things with our lives, but for a cell, what it really wants to do is be as efficient as it can in doing its job, be it producing energy or multiplying. Over billions of years, evolution has tried to ensure that a cell can extract maximum output from a minimum amount of energy input, in other words be as energy efficient as possible. We get our energy from food, plants get their energy from the sun, but eventually, at the cellular level, it all boils down to just one molecule – Adenosine Triphosphate or as it is more popularly known, ATP. ATP is the energy molecule of the cell, the fuel that drives all cellular processes including transport by dyneins. Dynein uses up one molecule of ATP for every step it takes on a microtubule. Considering the fact that microtubules are really long, that means using up anywhere between 75 – 100 molecules of ATP, and that’s only one way! Thus cargo transport by dyneins across microtubules is a highly energy consuming process and must be tightly regulated to ensure that ATP is not needlessly wasted. Gaining deeper insights into these regulatory mechanisms was the main focus of this study.

Using highly sophisticated optics and microscopy techniques, the researchers were able to show that dyneins are able to recognize whether or not they are carrying cargo on their tails. If they are, they can also sense the weight of the cargo they are carrying and alter the speed and force with which they move on the microtubule in order to maximize efficiency. Instead of a genuine cargo like DNA or a protein, the researchers gave dyneins an artificial one to carry - beads. A laser can sense a bead and hold on to it causing it to be ‘optically trapped’. By increasing the intensity of the laser, the strength of the trap can be increased, which tricks the dynein into thinking that it is carrying a heavier load. The step size of the motor and the force with which it pulls the bead can be determined by measuring the displacement of the bead from its initial starting point. When a dynein is not carrying any load, it moves at a gentle pace on the microtubule taking long steps averaging 30 nanometres. (Yes, 30 nanometres, 30 billion times lesser than a metre, but for a cell, that’s a sizable distance). As you begin increasing the weight of the load, the step-size begins to decrease from 30 nm to 15 nm and then all the way down to 8nm. But if step size is decreasing as load is increasing, isn’t the dynein becoming slower? As it turns out, dyneins aren’t that foolish. As the weight of the load increases, dyneins must also increase the force with which they are tugging at the cargo. They found that in the absence of load, the dynein tugs with a force of about 0.25 pN (pN stands for pico newton or 10-12 th of a newton. To put it in perspective, you would need one newton of force to accelerate a 300 kg wrestler into space at the speed of sound). But in the presence of a heavy load, that tugging force increases four times over to 1.1 pN. So the dynein sacrifices speed to ensure that it doesn’t lose its connection with its cargo. All this adjusting is because ATP is precious. If there were spare ATP lying around, dyneins would be happy to go as fast as possible while still maintaining contact with their heavy load. If it’s a lucky dynein though, and it realizes it indeed has a lighter weight on its back, it doesn’t need that much tugging force. Using what the researchers call a ‘power stroke’ it can ‘accelerate’ by shifting into ‘top gear’. We should probably have EA sports (the publishers of Need For Speed) make a dynein version, but they’ll have to rename it. Maybe they could call it… Need for Efficiency and Speed… or something equally geeky!

Original article:
“Cytoplasmic dynein functions as a gear in response to load”  Nature. 2004 Feb 12;427(6975):649-52.

 

Our cells eat themselves! Don’t panic! Not for harm, for good; but how?

By: Seda Barutcu

You did not misread it! That is right, our cells eat themselves. This may sound cannibalistic or savage at first, but I will show you how it is not different than recycling your papers. Moreover, believe it or not, scientists showed that this self-eating behavior of cells helps us to cope with diseases such as cancer, diabetes, infections and even ageing (1-3).

A new scientific report in the journal Nature showed another role of cells’ self-eating behavior: beneficial effects of exercise (4). Before I tell you what this report showed, I first need to introduce the term “autophagy”, which scientists use for cells’ self-eating.

As we eat our meals, sugars (building blocks of carbohydrates), amino acids (building blocks of proteins) and fatty acids( building blocks of fats) dissolve in our blood and travel inside our body, waiting to be eaten by cells. On the other hand, when we run for a couple hours or start on a diet, circulating food will decrease to insufficient levels for our starving cells. Now, it is time to recycle the wastes for more energy. Cells use many proteins, fats and carbohydrates for various purposes and when cells finish their duty, these molecules are no longer needed. When cells need recycling through autophagy, a membrane is built around the waste to lock it in an isolated compartment called autophagosome. To digest the waste, cells have small pouches called lysosomes, which have enzymes similar to ones in our stomach. When lysosomes combine with the autophagosome, that new pouch resembles a pot of fresh food filled with amino acids, sugars and other stuff that the cells are hungry for. Then the pouch breaks apart and the food is served to the cell.

That is the story of how our cells endure when we exercise or starve. Even when the cells are not starving, they have a basal level of autophagy. After all, it is always more beneficial to recycle rather than to send trash into the blood. If you want to know further about the molecular events in autophagy, there are proteins that regulate and organize this self-eating process. One of these proteins, beclin-1, is indispensable for cells to do autophagy. Another protein called BCL2 acts as a trap for beclin-1, and autophagy cannot start unless BCL2 releases beclin-1. In summary, when cells need more autophagy, they order BCL2 to release beclin-1. And beclin-1 allows autophagy to increase.

Now, we learned what we need to know, let’s start the story that Beth Levine and colleagues told in the Nature report. First, they wondered if autophagy increases in muscle cells when we exercise. They have a dye that can specifically stain autophagosomes and allow researchers to measure the level of self-eating by counting these stained vesicles in muscle cells under a microscope. They put a group of mice on a treadmill and had them run for a while. On the other hand, a control group of mice just continued their routine life during this time. Afterwards, they took muscle samples from both groups and measured the autophagosomes. Indeed, they found more autophagosome vesicles in the muscle cells after exercise!

Next, they wondered if they blocked autophagy in muscle cells, how this would affect the outcome or beneficial effects of exercise. They bred some mice in which the BCL3 protein was mutated so it never released beclin-1, even if a cell ordered it to release. As you can imagine, without free beclin-1 autophagy cannot increase in the cells of these mice. Then, they fed the mutant mice and normal mice with a high fat diet. This diet is like hamburgers and fries; it makes the mice fat and even obese in the long term. When they allowed the mice on the high fat diet to run on the treadmill daily, the normal mice didn’t get fat because BCL3 could release beclin-1 to increase autophagy and recycle the extra food components. On the other hand, the mutant mice on a high-fat diet did not get the autophagy-induced benefits of exercise. In fact, they got fat even though they exercised in the same way. Beth Levine and her colleagues showed not only the effects of autophagy on keeping the body lean, but -also that the protective effects of exercise against diabetes are also related to autophagy.

In conclusion, your muscle cells need to eat themselves for you to get the beneficial effects of exercise. Without autophagy, exercise is not as beneficial as it is supposed to be. Maybe this is the underlying reason for some cases of exercise resistant obesity in human. We don’t know yet, but it looks like it is worth digging into it further. Many compounds are already used to block or activate autophagy in cells for research purposes. Maybe in a couple of years some of them will become valuable for fighting obesity. Or maybe we will get pills to make our body feel the effects of exercise while we watch TV on our comfy couch. Who could say no to this offer?

REFERENCES:
1. Levine, B. & Kroemer, G. Autophagy in the pathogenesis of disease. Cell 132, 27–42 (2008).
2. Yang, L., Li, P., Fu, S., Calay, E. S. & Hotamisligil, G. S. Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance.CellMetab.11, 467–478 (2010).
3. Ebato, C. et al. Autophagy is important in islet homeostasis and compensator increase of b cell mass in response to high-fat diet. Cell Metab. 8, 325–332 (2008).
4. C. He, M. C. Bassik, V. Moresi et al., “Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis,” Nature, vol. 481, no. 7382, pp. 511–515, 2012.

 

40% of Cancers are caused by fragments of DNA that jump from their original place to another

By: Houda Belaghzal

In our body we have a lot of DNA, which carries our genetic information needed for development and function of every cell. In cells the linear DNA is organized and packed into chromosomes, and in each cell of our body we have 23 different chromosomes (genome). In each cell the genome is packed in a very organized way inside a very small pocket called the nucleus. Imagine the DNA packing as if you wanted to put your headphone cords in a round and very small pocket, but you do not want the cords to tangle. After genome packing, some pieces of the genome can interact with each other even if they were far away in the linear DNA (red pieces in figure 1a,1b).

HoudaBelaghzalBlogPic

In some types of cancers like leukemia (blood cancer) and thyroid cancer, scientists found that some pieces of the genome jump from their original locations to new locations, a process called translocation. Then scientists asked how translocation happens? And why does it cause cancers?

For translocation to happen, first two different pieces of the genome need to break, and then they exchange places. The breaks can happen for several reasons like when you expose your skin to a lot of sunlight or to artificial ultraviolet in a tanning booth. After the breaks, those pieces of DNA become unstable and try to reattach somewhere.

Why does translocation cause cancer? As I explained in my first paragraph, the way the genome is packed is not random, so a gene location has an important role in its expression. Some genes control the expression of the genes next to them or some other genes that are far away in the linear DNA, but they interact with them in three dimensions (3D; like the red spot in Figure 1). To explain why translocation causes many cancers, I will use an example. In our genome there is a gene called Myc, which controls cell division. In a normal person the Myc gene is tightly regulated by its neighboring genes, which makes sense because we do not want the cells in our body to divide a lot and increase the number of cells in a crazy way. In some cancers, cells divide much more than normal; the reason is that the Myc gene get exposed to breaks, then changes its original location in the genome. Myc reattaches next to another gene that makes it more active than it was in its normal location. For example, the Myc gene translocates in thyroid cancer, causing thyroid cells to divide abnormally to form a thyroid tumor.

Technology advances so fast that now if you have a smart phone, you can map the locations of some of your friends that also have smart phones. Could we do that for translocation in the human body? Scientists at the University of Massachusetts Medical School developed a technique in 2009 called Hi-C, which helped them to understand the 3D organization of the genome inside the nucleus. In 2012, that group of scientists collaborated with another group at Harvard Medical School to introduce DNA fragments into specific locations of the genome. They broke up those target fragments. Then, by using Hi-C method they mapped 3D images of where the target fragments reattached after they broke. The scientists observed that, if two neighboring fragments break they will join; however, if they are far away from each other they never join. Also they saw that if two fragments are near each other, but do not break they will never join. The conclusion from their study is for fragments of DNA to translocate, they should break first. Also they showed that the 3D organization of the genome influences the reattachment of the broken fragments of DNA.

Why should we care about that work? Those scientists showed that the 3D organization of genome influences the rearrangement of broken DNA fragments; they were able to map the translocation. Translocation in a normal cell causes some type of cancers; however, it takes on average 5 years after translocation for a cell to function as a cancer cell, and to start seeing the first cancer symptoms. By using that Hi-C technique scientists might be able to map any translocation in the genome, which may lead later to cancer. And the detection would be possible right after the translocation happens, which is a very early stage before any symptoms of cancer appear in the patients. That early detection would help for early treatments of the patient, which can increase the probability of curing cancer.

References:
Yu Zhang, Rachel Patton McCord, Yu-Jui Ho, Bryan R. Lajoie, Dominic G. Hildebrand, Aline C. Simon, Michael S. Becker, Frederick W. Alt and Job Dekker. Spatial organization of the mouse genome and its role in recurrent chromosomal translocations. Cell. 2012 Feb 16.
Rachel Patton McCord1 and Job Dekker1. Translocation Mapping Exposes the Risky Lifestyle of B Cells. Cell 147, September 30, 2011 
 

Why is Sally Sicker than Sue with the Flu?

By: Michelle Bellerose

Every year the influenza virus sweeps in during the cold winter months and infects between 5 and 20 percent of the population and hospitalizes more than 200,000 of these infected individuals. Different people react differently to the influenza virus. Therefore while catching the flu for Sue may mean a few miserable days spent on her couch, for Sally it may mean severe complications and a stay in the hospital. What causes these differences in symptoms?

Recent research, supported by the Wellcome Trust Sanger Institute and Ragon Institute of Massachusetts General Hospital, has identified a protein, IFITM3, which may be the key player in the symptom difference between individuals. IFITM3 is in a family of proteins that function as part of the innate immune system, the body’s first line of defense against invaders. After a pathogen is recognized the IFITM proteins are turned on and work to restrict the growth of viruses and help efficiently rid the body of the virus. Researchers demonstrated that without this key protein low-pathogenic flu viruses, which normally cause minimum symptoms, were able to cause severe symptoms usually only seen in highly pathogenic strains. To characterize the protein’s role in fighting the flu the researchers gave the flu to normal mice and mice that lacked IFITM3. When infected with low-pathogenic influenza virus mice with IFITM3 displayed minor symptoms and fully recovered; however, mice without IFITM3 developed severe symptoms including rapid weight loss and pneumonia. Mice lacking the IFITM3 protein had a large increase in growing virus and a decrease in the amount of active immune system components when compared to mice with the protein. This demonstrates that the severe illness observed is caused by a lack of immune control of the virus. Without this protein the first line of defense is weakened and the virus can take over early.

Following this, researchers wanted to know how this knowledge could provide insight about human infection with influenza. The gene that contains the information to make the IFITM3 protein in humans has two regions of information, called exons, which are separated by DNA that does not contain any information, called introns. When it comes time to make the protein, components of the body recognize a type of code, called a splice site, which means “cut here” and removes these unnecessary pieces. This allows different versions of the protein to be made. As we know, no two people have identical DNA; therefore the splice sites saying “cut here” for the IFITM3 protein can potentially differ between individuals. The researchers observed that while a majority of people had the same splice site, some people had a different version resulting in a removal of a certain piece of the protein. They then looked at samples from patients who had been hospitalized due to the flu and noticed that a larger portion of these hospitalized individuals than predicted made this shortened variation of IFITM3.

Could this shortened variation of the IFITM3 protein make a person more susceptible to flu? It seems that way. The researchers tested this idea by infecting cells with influenza that either encoded the full length protein or the shortened protein. Cells that made the shortened protein were more susceptible to viral infection and were also unable to prevent viral growth; this effect was seen with different strains of influenza virus ranging in pathogenicity. This evidence indicates that IFITM3 is a crucial barrier to block the influenza virus and that people who produce the shortened protein may be at a disadvantage in fighting the virus.

What does this all actually mean? While a persons’ genetics cannot be changed, this information helps identify groups at greater risk of severe flu infections both in a regular flu season and in a potential pandemic. Looking at different populations, the researchers observed a different frequency of this shortened protein within different populations; therefore not only is there a difference between individuals but there is also an overall frequency difference between populations. By identifying groups at high risk, more efficient steps can be taken to protect these individuals. This information is also beneficial to other research with different viruses; if IFITM3 is such a good defense mechanism against the flu, what else could it fight? These researchers additionally identified IFITM3 as a component involved in the defense against West Nile virus and Dengue virus. Whichever path researchers take, this information provides new insight. It provides the opportunity for better prevention and protection, not only against influenza but potentially other burdening viruses as well.

Everitt et al. IFITM3 restricts the morbidity and mortality associated with influenza. Nature 484, 519-525 (2012).  

Preventing cancer from spreading its evil wings

By: Numana Bhat

The worst face of cancer is metastasis- the process by which a tumor spreads to different parts of the body other than the tissue of origin. These secondary cancers are called metastatic tumors. Metastatic tumors are the principal cause of death by cancers. Metastasis occurs when cancerous cells escape the tumor and travel to other parts of the body via the blood vessels and lymph vessels that innervate the tumor. However, since a cancerous tissue is an abnormal tissue, its plumbing is different from normal tissues. A tumor is a tight mass of tissue, therefore the pressure inside it is high which causes the blood vessels and lymph vessels to become leaky such that cancer cells enter these vessels and form small nodules in them which develop while they are still travelling through these vessels. These potential tumors are called “in-transit” tumors and they get implanted in other organs and establish cancers there. Lymph vessels are the major partners in crime to these “in-transit” tumors as these vessels drain the tissue, including cancer cells and nodules, and hence take material away from them to the rest of the body.

The general treatment for tumors is surgical removal which removes the established tumors. This is followed by chemotherapy and/or radiotherapy which kills the remaining cancer cells and potential tumors. But, you can’t have the cake and eat it too! Since radiotherapy and cancer therapy are non-specific in their mode of action, these inadvertently damage normal tissues of the body too. This is obviously not the best thing to happen. We need a treatment or a combination of treatments which removes the cancer and specifically destroys the remaining cancer cells and potential tumors which include the in-transit tumors.

Tammela and team, a group of science warriors fighting against cancer, in their quest to find such a treatment, studied the effects of a combination of light therapy and a drug called verteporphin on metastatic cancers. They implanted mice with a tumor in the ear and allowed the tumor to grow to a certain size so that lymph vessel networks form in them, which is the normal course of tumor development. They then looked for the formation of in-transit tumors and confirmed their development, and injected the mice with verteporphin which enters the lymph vessels in the tumor. They followed this by shining light of a specific wavelength on the tumor. The light converts the drug into a highly reactive molecule which destroys the tumor. They observed that the tumors shrank in size and died freeing the mice of the tumor. But, the question that remained was whether the tumor would relapse or not. To study that, the research group looked at the effect of this combination therapy in mice that had undergone surgical removal of these tumors and compared the outcome to mice in a similar setting in which they surgically removed the tumor but did not follow up with the combination therapy. They monitored tumor relapse in both groups of mice and observed that the mice which had received the combination therapy did not form cancers again.

While Verteporphin has been previously used to destroy blood vessels surrounding the cancerous tissue but not the vessels far away from it (the vessels far away may not be any less dangerous in terms of carrying potential cancers!), neither has anyone used the light therapy in combination with this drug. This combination of treatments is a new idea to get rid of any traces of cancerous tissue anywhere in the body, prevent recurrence of cancer, and hence, is a great idea!

This group of scientists performed similar experiments in pigs and the outcome concurred with that seen in mice. This treatment has not been tested in humans so far, but if tested in humans and found to work in us too, this will give a hope to all those suffering from this terrible disease and many death due to metastatic cancers may be prevented. This may mean that the dream of the proverbial “cure for cancer” may soon turn into a reality!

Reference: Photodynamic Ablation of Lymphatic Vessels and Intralymphatic Cancer Cells Prevents Metastasis; Science, Tammela et al., 2011

 

A new hope for Huntington’s disease relies on stem cells

By: Mehmet Faith Bolukbasi

In our modern world, the field of medicine cannot provide a cure for many diseases. However, life scientists are putting every effort into establishing the future of medicine which will rely on next-generation therapies.

One such example of a next-generation therapy against Huntington’s disease (a heritable disorder where the nervous system and brain of patients progressively degenerate) has just been reported in the journal Cell Stem Cell. Researchers at the Buck Institute for Research on Aging have used a stem cell-based genetic correction approach to revert the genetic defects causing Huntington’s disease (HD) back to normal [1]. Although the story sounds like science fiction, the underlying rationale of the study makes it legitimate. Before diving into the details of the study, let’s start with the basics to set the stage.

What are stem cells?

Stem cells are a small subgroup of cells that have the abilities to renew themselves, divide infinitely, and convert themselves into different cell types (such as blood, skin, bone or nerve cells). There are two types of stem cells: embryonic stem cells (ESCs) and adult stem cells. ESCs exist in early embryos (fetus) and they are pluripotent, meaning they can convert into any cell type found in the body. On the other hand, adult stem cells are located in bone marrow or some other tissues but they can only convert into limited cell types. This conversion ability is very important because certain cell types (such as nerve cells, brain cells) do not divide throughout the life time of an individual. Consequently, a person can have the maximum number of healthy brain cells at the time of birth. Although stem-cell studies started more than a decade ago, the progress has been slow because of the moral issues. Harvesting ESCs from a fetus (an unborn baby) is considered murder for most people, and this has been the major obstacle so far. Wonderful news was announced a few years ago suggesting that adult body cells can be converted back to stem-like cells [2]. Since harvesting of such cells (called induced pluripotent stem cells- iPSCs) does not require any unborn babies, it is ethically safe. Besides, iPSCs are person specific. Shortly after the announcement of iPSCs, stem cells became popular again in regenerative medicine, a field that aims to replace damaged organs or tissues with healthy ones [3].

What is Huntington’s disease (HD)?

Huntington’s disease, which affects about 30 thousand people in the US [4], is a hereditary brain disorder where patients experience problems in their muscle coordination and intellectual abilities (e.g., speaking, problem solving) because their brain cells are degenerated to die. Since healthy brain cells cannot divide to replace the dying ones, the condition of patients gets worse over time. HD occurs as a result of a dominant mutation (change in the genetic material) in the huntingtin gene. This means that patients have one healthy and one mutant copy of the huntingtin gene within their genetic material. Presence of one mutant copy is sufficient to cause HD. What is worse, if a parent has the mutant copy, each of his/her children has a 50 percent probability of getting HD.

The researchers at the Buck Institute generated induced pluripotent stem cells from the adult body cells of Huntington’s disease patients. Then, they genetically manipulated these iPSCs so that mutant copy of the huntingtin gene was replaced with a healthy functional copy of the gene. In order to do so, the researchers took advantage of a phenomenon called “homologous recombination”. As the name indicates, it is a recombination process within the genetic material. The adjective “homologous” means that such recombination takes place within regions that are similar. Upon reversion of the mutation via homologous recombination, these manipulated iPSCs can still convert themselves into functional cell types, including neurons in cell culture. Furthermore, the researchers showed that after genetic conversion, abnormal cellular events -such as defects in mitochondria (a cell compartment that produces energy for the cell) or changed levels of certain proteins- also change back to normal. As a result, nerve cells no longer have the properties of the damaged cells, and they no longer die. These results provide a novel model for future therapeutic applications in HD.

Although the outcome of this study is very promising, it is still too early to cheer up. The current finding is a critical step to setting the stage for future stem cell-mediated replacement therapies. The good news is that stem cell-based therapies are not only the new hope for Huntington’s disease, but also other diseases.

References
[1] M. C. An, N. Zhang, G. Scott, D. Montoro, T. Wittkop, S. Mooney, S. Melov, and L. M. Ellerby, “Genetic Correction of Huntington’s Disease Phenotypes in Induced Pluripotent Stem Cells.,” Cell stem cell, pp. 253–263, Jun. 2012.
[2] K. Takahashi and S. Yamanaka, “Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.,” Cell, vol. 126, no. 4, pp. 663–76, Aug. 2006.
[3] S. Yamanaka, “Induced pluripotent stem cells: past, present, and future.,” Cell stem cell, vol. 10, no. 6, pp. 678–84, Jun. 2012.
[4] I. Shoulson and A. B. Young, “Milestones in huntington disease.,” Movement disorders : official journal of the Movement Disorder Society, vol. 26, no. 6, pp. 1127–33, May 2011.

 

 

White matters: Protecting nervous system wiring

By: Thomas Burdett

In the course of history, humans have sought to protect their brains from trauma, disease, and aging via diverse strategies such as helmets, herbal remedies, and medicines. These ‘neuroprotective’ strategies continue to be applicable today. Our increasingly aging population suffers through neurodegenerative diseases like Parkinson’s and Alzheimer’s, while our athletes and soldiers deal with the effects of traumatic brain injuries from concussive impacts to the head. Diseases or trauma often lead to a buildup of toxins or structural failure that subsequently overwhelms our fragile brain and nerve cells, called neurons. Neuronal death, however, is not a passive process. Once overwhelmed, each cell decides to commit suicide by activating its own internal death program. Attempts to protect or prevent cells from their own death program, called apoptosis, yielded mixed results.

Therapeutic failures can be attributed to the complex nature of the nervous system and diversity of neurons within it. One could think of the human nervous system functioning in a similar manner to the internet where millions of computers communicate to each other through a huge network of cables and wires. Computers represent central bodies of the neurons that control cell functioning and communication, while the connecting wires represent very lengthy processes, called axons, that project from cell body to carry information to distant neurons. If a cell body was the size of a three story apartment building it could have an axon approximately one foot wide stretch from Boston to New York. These lengthy axons are found both in the brain, in what is termed white matter, and connecting the brain to muscles and organs in the body.

Unlike the internet, however, an axon severed from the cell body proceeds to breakdown and be cleared by other cells. This degeneration was named after Augustus Waller’s observations of axons fragmenting in sliced frog nerves way back in 1850. Since the cell body lost its connection to the axon, Wallerian degeneration was theorized to be a consequence of nutrient deprivation. This was the prevailing theory until 1989, when Lunn et. al. discovered a mutant mouse in which axons failed to fall apart upon cutting or axotomy. This mutant mouse provided the first hints that axon degeneration played by a completely different set of genetic rules than programmed cell body death.

Osterloh et. al. from the Freeman Lab at UMass Medical School built upon these clues in a recent Science paper entitled, “dSarm/Sarm1 Is Required for Activation of an Injury-Induced Axon Death Pathway.” To find the protein dSarm (short for Drosophila (fruit fly) Sarm), researchers in the Freeman lab performed an exhaustive forward genetic screen. While human geneticists search for rare disorders conserved through family trees, fruit fly geneticists can create their own mutant fly families with mutagens. Basically, they used a substance similar to the green ooze that gave us Teenage Mutant Ninja Turtles. The mutants fly families, or stocks, generated had already been genetically manipulated to express a glowing green marker in a specific type of neuron. These green neurons had cell bodies situated in the fly antennae and axons projecting to the smell center or olfactory bulb of the brain. Researchers could then simply rip off a fly antenna to destroy cell bodies and observe how the green axons died off. Simplicity is especially important in this sort of experiment since researchers then had to screen through the thousands of mutant fly stocks they created earlier. In normal flies, green axons disappeared in a few days after axotomy, while axons persisted for almost a lifetime in flies lacking a functional copy of dSarm gene.

It is important to note that evolution builds off previous success rather than starting from a blank slate for each species. Building blocks that led to the first simple nervous systems were present in a common ancestor of fruit flies and humans. Remarkable conservation of these components allows researchers to apply most discoveries in fruit flies to mammals. In this vein, Osterloh et. al. found a mammalian gene similar to dSarm, named Sarm1. By creating a mouse which lacked Sarm1, they confirmed Sarm1 also governs an axon death program in mammals.  The discovery of Sarm1 is an important first step to elucidating all of the genes that dictate the rules governing axonal degeneration. New genes will be found as forward genetic screens in fruit flies continue. Each component of the pathway could be an important target for new treatments. Axon-specific neuropathies such as ischemic stroke, multiple sclerosis, glaucoma, and trauma could be corrected with drugs stopping these pathways. Parkinson’s disease could also be treated by inhibitors as it involves neurons which proceed to die back from axon to cell body. Future discoveries of axon death components will add to our knowledge of how the brain degenerates and how it might be protected.

 

Blind mice see light: bring a ray of hope to blind people

By: Hsin-Rong Chou

Imagine you are awake on a sunny morning: you can feel the sunshine even with your eyelids closed, and then you open your eyes, look around, and finally get up out of your bed and walk to the bathroom. In the meanwhile, tons of cells in your eyes are busy doing hard work to introduce the world to you. When light passes through your eyes as a light beam, it eventually focuses on the retina, a layer in the back of eyes and full of different types of neurons that cope with light signals and send them to the visual area in the brain. One special type of neuron in the retina has the ability to receive light, convert light into nerve signals, and transmit the signals to other types of neurons in order to send the signals to the brain. These special photo-sensitive neurons are called rod cells and cone cells, or rods and cones for short, serving as the first-line neurons to receive information from outside the eyes.

It is not hard to picture that a person without rods and cones feels like he or she lives in a dark chamber, not able to see anything. A blinding disease called retinitis pigmentosa, affecting 1 in 3,000 people over the world, results in the progressive death of rods and cones starting in childhood and continuing through adulthood. Patients with this disease have weak vision and eventually become irreversibly blind. One vision-protective method for these patients is to wear sunglasses to protect their retina from ultraviolet damage and slow down the process of being blindness. However, there is no effective treatment to date.

A research group led by Professor Richard H. Kramer at the University of California, Berkeley reported a small molecule which can restore vision in blind mice, thus giving hope to patients with retinitis pigmentosa. The research group applied the small molecule to retinas isolated from blind mice with the disease and measured the light response of a specific group of neurons in the retina. This group of neurons is called retinal ganglion cells. They serve as a final light-signal transmitter in the retina and have connections between the eyes and brain, enabling them to transfer information about light, shapes, and colors of objects to the brain. The retinal ganglion cells respond to light by “firing,” which represents changes of voltage between the outside and inside of the cells when they receive signals from other neurons. As they are firing, they consequently have a great chance to pass down the signals to other neurons.

The retinal ganglion cells in retinas isolated from the blind mice showed little firing when light shone on them, meaning they did not receive the light signal, mainly because of the death of rods and cones. However, the firing level promptly increased in response to light after the small molecule was applied. This indicates that the light signal can somehow be sent to retinal ganglion cells even without the photoreceptor rods and cones. The light signal then can be transmitted to the brain, leading to visual neurons firing in the brain.

So what is the big deal if neurons in the retina isolated from blind mice show firing? Can the mice really see light after treatment with the small molecule? The answer is inspiring. After injecting the small molecule into the eyes of living blind mice, they began to sense light by showing that they preferred to go to a dark room rather than a light room, which is a natural habit of mice. The result from another behavioral test also showed that the mice can sense light—mice treated with the small molecule began to display less willingness to walk in a bright and open space, which is another natural habit of mice to be safe from predators. These behavioral tests add solid evidence that the blind mice were able to see light after treatment with the small molecule.

This new strategy of restoring visual function suggests a prospective treatment for patients with this blinding disease. Until the research was done, scientists had developed various strategies to restore vision in mouse models, but all of them involved invasive surgery or risky virus infection. This encouraging research using a small molecule as a treatment may provide a safer and less invasive strategy to cure blinding diseases.

Reference:
A Polosukhina, J Litt, I Tochitsky, J Nemargut, Y Sychev, I D Kouchkovsky, T Huang, K Borges, D Trauner, R N V Gelder, and R H Kramer. Photochemical Restoration of Visual Responses in Blind Mice. Neuron (2012) 75, 271–282.

Old Dogs with New Tricks: How Platelets May Talk to Our Bodies

By: Lauren Clancy

In the world we live in today, science predominates much of the news, whether because of technological breakthroughs, political arguments or medical wonders. In the last century, the scientific field expanded greatly due to the development of new technologies. These techniques supplied scientists with the ability to tackle previously unattainable questions. Due to these advancements in understanding, one may wonder when science will progress so far that we will understand the entire world around us. Some even question the financial support governments continue to provide for scientific research, not understanding the benefits of continued study. To these people, I present the platelet, the small particulate-like cell of the bloodstream that, despite its long history, still surprises scientists today.

Accounts describing platelets date back to the end of the eighteenth century (1). These small cells break off from their larger parental cells, megakaryocytes, and circulate throughout your body. Unlike all other cells, platelets lack a nucleus, or the region of the cell normally holding its DNA or “genetic blueprint”. Based on this “genetic blueprint,” each cell produces compounds that determine the cell’s contents and functions. Without their own DNA, platelets rely solely on their parental cells to package them with the compounds they need to properly work. Since they can’t alter their content, scientists originally thought platelets couldn’t alter their function and wondered what these small cells could do in the body. By the end of the nineteenth century, scientists discovered these cells mainly function in clotting, preventing bleeding after injury or creating the clots that lead to cardiac disease and stroke (1). For the next hundred years, platelet research only focused on these two main roles. Since platelets couldn’t alter their predetermined functions through traditional methods, the scientific field assumed that platelets couldn’t do anything beyond clotting, a sort of “one trick pony”. However, recently scientists studying platelets realized that though they do not contain the original “blueprints” required for large cellular changes, platelets do contain RNA, duplicate “blueprints” of some of the original DNA, put in platelets by their parental cells. RNA can convey the original design set out by DNA, allowing platelets to make new compounds, change their contents and thus possibly change their functions. This discovery opened the field to the idea that platelets may participate in other functions throughout the body. Analyses quickly revealed roles for platelets in a wide variety of diseases such as cancer, infection and arthritis (3).

A recent study by Antonina Risitano and her colleagues focused on one of these new non-traditional roles for platelets (2). Risitano looked at the capacity for platelets to transfer information from themselves to other cells. Previous studies showed that other cells in the body could release small fragments of themselves and transfer RNA to target cells as a form of communication. The target cells used transferred RNA in several ways, such as for a template to make new compounds or as a signal to make other compounds in the target cells, both leading to altered cell function. Since platelets contain RNA and move throughout the body, the thought that they could act like these cell fragments became possible. Platelets could use the body’s own highways of blood vessels to communicate with different types of cells, especially those lining the blood vessel walls. Platelets cannot grow outside of the body, so for her studies, Risitano and colleagues used cells equivalent to platelet parental cells which can be grown in a lab. Using these cells, they created artificial platelets, or platelet-like particles (PLPs), previously shown to act like platelets. They introduced a fluorescent RNA molecule into the parental cells and then triggered their production of PLPs. They then isolated these PLPs and placed them with the growing cells equivalent to those that line blood vessels (representative of platelet target cells). By monitoring the fluorescence signal, they observed RNA moving first into PLPs from the parental cells and then into the target cells grown with PLPs. They showed PLPs directly transfer new, functional RNAs into the target cells. They even demonstrated this transfer occurs in animals. They introduced PLPs into a mouse model that doesn’t contain a specific RNA and then showed the presence of this RNA in mouse cells. The RNA in the mouse cells could have only come from the PLPs, supporting the transfer of the RNA from PLPs to the mouse cells.

This work supports the idea that platelet RNA transfer may occur in humans and may explain how platelets now seem to function in so many different capacities. It completely changes how science will think of platelets and what they can accomplish. Platelets may travel throughout the bloodstream, transferring RNA to different cells, setting up a communications system throughout the body. Considered alongside the knowledge that platelets function in many different diseases, this RNA transfer may explain how platelets act in disease states. It also opens up opportunities for developing treatments in these diseases. One could imagine taking a person’s blood, altering the message in their platelets and then giving them back to the patient in an effective, patient-specific treatment; in a way, allowing doctors to directly “talk” to the cells affected by the disease.

Beyond the advances that platelet communication presents for understanding platelet-related diseases and treatment, another important idea comes to mind thanks to this study. Scientists discovered platelets centuries ago but for nearly a hundred years we thought we had everything figured out about what they did. Now, the possibilities could be endless for how these little cells affect and direct the cells in our body and how science can use them to help improve people’s lives. It puts a spotlight on exactly why scientific pursuit needs continued funding and support – you never know what answers may lay, even in the tiniest, most unlikely places.

References:
(1) Michelson, AD. Platelets (Second Edition), Elsevier © 2007
(2) Risitano, A., Platelets and platelet-like particles mediate intercellular RNA transfer. Blood, 2012. . 119(26): p. 6288-95.
(3) Leslie, M., Beyond Clotting: The Powers of Platelets. Science, 2010. 328(5978): p. 562-4. 
 

A New Hope for Rooting Out Cancer: Targeting its Stems

By: Noah Cohen

In a highly controversial new paper in the journal Nature, scientists at the Université Libre de Bruxelles in Belgium, have traced the genetic lineage of cancer cells and found that they propagate in a manner remarkably similar to healthy cells. This finding significantly supports the hypothesis that a subset of cancer cells proliferates in a manner similar to stem cells to allow the formation of tumors.

The cells in a fully developed human body are the end result of cellular differentiation. This process is remarkable in that it allows a single-cell, the fertilized egg, to split into highly diverse and well defined cellular types, each with a specific function and form. This is accomplished through the use of stem cells, cells that are capable of differentiating into many types of cells. Cancer cells hijack this system and cause rapid, uncoordinated cellular division. It has long been debated whether or not cancer cells replicate in a manner similar to our own; that is whether or not cancer makes use of stem cells to propagate.

Many experiments observing Cancer Stem Cells have been performed under specific conditions not relevant to patient tumors, but they have never been observed inside of a living tumor; that is, until now. In this paper a series of experiments were performed allowing the researchers to examine the progression of tumor growth in squamous skin tumors.

The authors of this paper developed a specific method of marking cells with genetic markers such as Yellow-Fluorescent Protein (YFP), which fluoresces yellow, attached to specific genes. This allowed the experimenters to track the expression of oncogenes, which are genes that are expressed in greater amounts in cancerous cells. Addition of alternative markers such as BrdU, a DNA specific label incorporated during DNA replication, allowed the tracking of specific cell types. With these two markers, the authors could examine the expression levels of oncogenes in cancer cells as well as follow each cell’s lineage.

This method was applied to normal squamous skin cells first as a control to ensure that the authors had not altered cellular behavior with these techniques and then was applied to squamous skin cell tumors. The authors then tracked the lineage of the labeled cells to determine whether each cell monitored divided continuously, like normal cancer cells, or if a specific subset was more prone to division than others. The authors found that a large percentage of the cells monitored had a limited ability to proliferate while a small percentage persisted much longer and the progeny of these cells ended up comprising a large portion of the tumors. With further experiments, the author determined that the more proliferative cells had traits commonly attributed to stem cells.

This represents a huge advancement for cancer cell research. Future research can now focus on identifying the differences between Cancer Stem Cells and less proliferative cancer cells. This will provide a method for further understanding the process by which cancer growth occurs. Additionally, this finding may allow future researchers to identify the mechanisms that allow cancer to spread throughout the body by observing the life cycles of these Cancer Stem Cells and observing their invasive potential. Further research remains to be done, as this was all performed using specific cell lineages and even more controversially, a single specific tumor type. It remains for the authors, or others, to determine whether this behavior is occurring in all forms of cancer, or if it is a specific feature of this type of squamous skin cancer. In fact, this remains the most controversial part of the research, as cancer is known to be a highly diverse disease, which often takes a unique form even between patients suffering from the same type of cancer.

However, if this is a trait of all cancer cells, then the more important part for the majority of the world are the implications of this research in future cancer therapies. This research provides a new target for cancer therapies as eliminating the Cancer Stem Cells in patients would be more effective at preventing the spread of cancer throughout the body than would eliminating the less proliferative cancer cells. If a method of delivering anti-cancer drugs specifically to these Cancer Stem Cells can be developed, then a much lower dosage of drugs will be required to effectively treat patients, which would serve to decrease time spent in therapy as well as the overall cost of the treatment. Furthermore, if a fluorescent labeling technique similar to the ones used in this paper can be adapted for use in patients and that specifically targets these Cancer Stem Cells, then using nothing more than a specific type of light bulb could make a patient's tumor fluoresce. This would greatly assist surgeons in ensuring the removal of tumor cells responsible for reappearance of cancer. This would greatly increase the time patients suffering from cancer spend in remission, which would be a huge success in the battle against cancer.

Reference:
Driessens et al. 2012. Defining the mode of tumour growth by clonal analysis. Nature. doi:10.1038/nature11344
 

A New Type of Fat That Can Make You Skinny

By: Andrew Peter Converse

For decades science classes everywhere have taught students of the existence of two types of body fat, white fat and brown fat. White fat is the fat most people are familiar with. It is found under the skin (subcutaneous) and around internal organs in distinct collections or depots. It stores excess energy when you visit too many all-you-can-eat buffets, it balances beer cans on guys stomachs and it forces women to ask if they look good in a particular dress. White fat can also release hormones that cause inflammation and tell the body to eat more and store more white fat. This has the potential to cause a self-perpetuating cycle of disease. White fat, along with poor diet and lack of exercise, is responsible for the obesity epidemic sweeping the globe.

Brown fat is less well known than its white counterpart. This fat type was only found in young and hibernating mammals, until recently. Brown fat has undergone reexamination this past decade when researchers found the forgotten fat type in adult humans. The brown deposits are separate from white and the largest can be found on the back between one’s shoulder blades and under the collarbones. Brown fat is rich in the energy producing cellular organelle mitochondria, which gives it its brown color. These mitochondria contain high levels of a protein (UCP1) that enables it to carry out its function. In sharp contrast to White fat, brown fat burns energy and has a heat producing (thermogenic) effect. Think of brown fat as a fuel source like coal. When mammals become cold and can’t wait for a meal to obtain energy, their bodies recruit brown fat to burn energy. The energy, like the burning coal, can take the form of heat. This protects against hypothermia and also helps fight obesity and metabolic disorder by burning excess energy rather than storing it. It was recently determined that brown fat comes from a muscle-like cellular lineage.

New research published in the journal Cell describes the discovery of a new type of fat, called “beige” fat. An international team led by Bruce Spiegelman, a professor of cell biology at Harvard Medical School and Dana-Farber Cancer Institute explain that beige fat resembles white fat cells, but responds to stimulation like brown fat. Beige fat actually burns calories, like brown fat, rather than storing them, like white fat. It is found within white fat deposits beneath the skin, but has the ability to produce high levels of the mitochondrial protein (UCP1) like brown fat. However, this beige fat is not derived from the muscle lineage like brown fat. So this is a unique type of fat that is not produced the same way the classical fat cells are produced.

Spiegelman’s group discovered a hormone (irisin) earlier this year that is secreted by muscle cells. This hormone is secreted at especially high levels during exercise, and causes the conversion of white subcutaneous fat to brown-like fat. Their latest data suggest that beige cells are preferentially sensitive to this hormone. They also determined that rather than making white subcutaneous fat act like brown fat, the hormone is actually stimulating a unique type of fat that usually looks like white fat but can behave like brown fat. Think of this hormone like a light switch in the body. A person goes to their local gym, finds a treadmill next to the guy in a dripping wet sweat suit and begins their daily jog. During the exercise, the person’s muscles start producing the hormone irisin. The hormone enters the bloodstream and travels to white fat deposits where it signals the inactive beige fat to turn on and start burning energy.

They have shown that this energy-burning beige fat exists in both mice and adult humans. In fact, the data indicates that the brown fat found in adult humans contains specific genetic markers that make it resemble the beige fat more than classical brown fat in mice. This new work is vital, as it will give new insight to the molecular characteristics of this new type of fat cell. They are currently investigating techniques to target and activate these fat cells to combat obesity and diabetes.

Being Adipocytes Are a Distinct Type of Thermogenic Fat Cell in Mouse and Human, Wu et. al. , Cell July 20th , 2012.


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