Communicating Science Course 2012 Blogs
Mothers carry her baby’s cells long after giving birth
By: Nick Hathaway
Have you ever felt badly about all the trouble you gave your mother as a child? Recently, researchers have shown that you may have been giving her grief ever since you born. Researchers see that during pregnancy, fetal cells, cells that belong to the baby while the baby is still in the womb, migrate and stay in the mother’s bloodstream long after she gives birth. Even though researchers have known this for the last decade, it wasn’t clear what type of fetal cells migrate to the mother. A recent study lead by Dr. Diana Bianchi at Tufts Medical Center aims to identify the fetal cell types using new techniques to better understand the role the fetal cells might be playing in the mother’s health.
The study is published in the June 2012 issue of Biology of Reproduction and uses techniques to identify DNA from fetal cells taken from mother mice’s lungs to identify the cell types. Previous studies have used techniques to identify fetal cells by looking at markers found on a cell’s surface. Each cell has several markers on its surface and cells can have a specific mix of markers that can be used to identify them. However, identifying cells using DNA can be more specific about the type of cell it is. The researchers found that the fetal cells mainly consist of three different kinds of cells: trophoblasts (cells that derive from the placenta and help to provide nutrients to the fetus), mesenchymal stem cells (cells that have the potential to turn into bone, cartilage, and fat), and cells of the immune system. Researchers suspect that the presence of the fetal cells help to give the mother’s immune system tolerance to the fetus.
During pregnancy, the mother’s immune system would recognize the fetus as foreign and could lead to a potentially fatal attack on the fetus by the mother’s own immune system. The researchers theorize that since some of the fetus cells that migrate to the mother are immune system type cells, this might help prevent this attack from happening. This is supported by an increase in fetus cell migration the more the fetus and mother cells differ. The more the mother and fetus cells differ the greater the chance of the mother’s immune system attacking the fetus, so if this theory is correct this increase in fetal cell migration might help prevent the attack. The discovery of these immune system cells should help future researchers investigate the effect these cells have on the mother’s immune system during pregnancy and beyond.
Though the migration of the immune system type cells is in the fetus’ best interest, it seems the migration of the mesenchymal stem cells provide great benefit to the mother’s health long after she gives birth. This finding supports previous research efforts and helps to provide further evidence for the benefit these cells have on maternal health. These cells have the ability to turn into several different cell types and have been found to migrate to sites of injury in the mother. There, they help to replace cells that been damaged or lost and can help heal the injury to the mother and with their ability to turn into several different types of cells these cells can help heal injuries to multiple organs and even bone.
Although benefits of fetus cell migration have been found, not all has been found to be beneficial. The migration of trophoblasts from the fetus, which are cells derived from the placenta, have been implicated in a condition called preeclampsia. Preeclampsia is a medical condition affecting mothers during pregnancy that is marked by a dangerous increase in blood pressure that can be harmful to the both the mother and fetus. Therefore being able to identify these cells in the mother’s circulation could help to indicate to monitor more closely for this condition and help prevent the lost of life.
These findings have helped further the understanding of the effects of pregnancy on women’s health and have added new tools to study the effects further. The new techniques developed by Dr. Diana Bianchi and her team should be a great help in discovering the effects of fetus cell migration, be it helpful or harmful.
What Your Father Ate Can Affect What You Will Be
By: Tsung-Han Hsieh
What will you have for your lunch? French fries, hamburger, or a plate of salad? No kidding, although it sounds like the plot of a fiction movie: the food you eat does not affect only yourself; it could also determine how your children will be. Dr. Oliver J. Rando and his research group at the University of Massachusetts Medical School discovered that different diet preferences of paternal mice can affect the metabolic system in their offspring – which means if your father loves to eat healthy, low-cholesterol, and low-calorie food, you have a higher possibility of becoming a slim and healthy guy; if not, you should pay more attention to your health exam report.
DNA (deoxyribonucleic acid) is a genetic molecule which consists of four different basic units – A, T, C, and G. Since Watson and Crick solved the mystery of the genetic code in 1953, we know that these basic units in DNA encode the genetic information for our characteristics, such as hair color, eye color, and height, which can be passed on to our children. However, the question emerges – how do we pass our newly gained abilities to our children for adapting to changes in the environment? According to Darwin’s theory of natural selection, organisms generally adapt to new stresses in the environment by spontaneous changes in the basic DNA units (mutations) over thousands of years – which means that DNA is impossibly altered within only a few generations to improve our living quality in the new environment. But it sounds weird, right? Everything changes so fast in the 21st century. Even though carbon dioxide in the atmosphere goes up, temperature fluctuations make people crazy, and junk food shows up everywhere, humans still live well on the planet. We still look good. What is going on? What’s wrong with Darwin’s theory?
Here comes a new field called epigenetics, which adds another layer of inheritable information to the genetic code. Epigenetic inheritance means that cells can inherit genetic information or a cellular phenotype without any changes in the order of basic units of DNA. Let’s simplify it – imagine DNA as a rope that we can fold into thousands of shapes and mark with some colorful labels. If these shapes and labels can be inherited by future generations with high fidelity as DNA, we name these processes epigenetic inheritance. The folds of rope we call chromatin structure and the colorful markers we call DNA methylation, which means that a chemical group is to one of the basic units on the DNA. Although we have understood that additional information can be carried to future generations by the epigenetic process, no one knew for certain whether mammalians could pass traits which were adaptations to changes in a new environment directly to children via epigenetic inheritance.
Oliver Rando and his research team verified that father mice’s diet can affect cholesterol and lipid metabolism in offspring through an epigenetic process. This study was published in Cell. The story begins with male mice being fed normal or low-protein (to mimic a hungry condition in mice) diets from the time they were weaned until they reached sexual maturity. Mice on both diet conditions then mated with female mice reared on a normal diet. Rando’s team analyzed the whole gene expressions in offspring of mice on the two diet conditions, and found that many genes belonging to lipid biosynthesis, steroid biogenesis, and cholesterol biogenesis were upregulated in offspring from fathers fed a low-protein diet. This means that, as the fathers did not get enough protein before mating, some signals could pass to children and alert them to regulate their metabolic pathway to adapt to changes in the environment. The signal is something like, “Hey boys, the living environment is pretty bad. I’m so hungry every day. I suggest that you increase your ability to produce lipids and cholesterol by yourself.” How does a father tell his children to make changes? Epigenetic profiling in mouse offspring livers identified changes in DNA methylation at a region critical to a gene expression that relates to lipid biogenesis. The DNA methylation occurred at the basic unit cytosine, acting like a label on the DNA that can be passed down to offspring. Therefore, fathers can send a signal responding to environmental changes to children through epigenetic inheritance, but without changing DNA sequence.
What do you want to eat for your lunch? Think twice, you can choose something healthy for yourself and your future children. Go to eat vegetables, fruits, or a nut mix. Hamburger and pizza? No, thanks.
Carone BR, Fauquier L, Habib N, Shea JM, Hart CE, Li R, Bock C, Li C, Gu H, Zamore PD, Meissner A, Weng Z, Hofmann HA, Friedman N, Rando OJ. Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell. 2010 Dec 23;143(7):1084-96.
A viral infection that doesn’t kill you, doesn’t make you stronger
By: Arvin Iracheta-Vellve
How often do we hear that what we once thought to be good for you turns out to cause cancer? We have been told that red wine is good for you, but later told that all types of alcohol are bad for you. Then, scientists claimed that the tannings in red wine likely don’t determine your life span after all; it is all determined by your genes, not your bar tab. These mixed opinions come from scientists that seemingly can’t keep their story straight. Now, even our immune system has taken a page off the old Scientist Handbook. Our body’s response to infection enables us to develop immunity, but the immune response to viral attacks may not be as good as previously thought; an attempt to fight off viral infections may actually lead us to be fatally susceptible to bacteria.
It has long been known that upon infection by a virus, such as the common cold, the elderly and patients with compromised immune systems are more likely to develop a bacterial infection. More specifically, it has been well documented for over 100 years that there is a surge in mortality during influenza epidemics due to the associated complications of bacterial pneumonias. This increased incidence or severity of bacterial co-infection is especially true for those prone to infections, where even seemingly mild bacterial infections often be life threatening.
Physicians have historically attempted to combat this ‘lethal synergy’. To prevent a bacterial attack in weak patients with viral infections, the typical approach is to aggressively treat with antibiotics while advocating for vaccinations as a preventative measure. Even though it is known that the immune system is activated during a viral infection, physicians and researchers have never understood the underlying cause that makes the body vulnerable to bacterial infections.
In last month’s issue of Nature Immunology, a leading scientific journal, researchers showed that IRF3, which is critical in activating genes tailored specifically to combat viral infections, also suppresses the ability to fight bacterial infections. This dual effect of IRF3 –boosting the antiviral while suppressing the antibacterial immune response – is the underlying reason for our susceptibility to bacterial infections after a viral one.
When immune cells sense a viral infection, IRF3 is activated via a series of relay signals that lead to the production of antiviral interferons. Similarly, IRF5 is activated upon sensing patterns associated with bacterial infections but leads to an outcome specifically tailored to fight bacteria with the production of important antibacterial proteins called interleukin-12 (IL-12).
Previous studies have shown that these activated signaling pathways can interact with each other in a variety of ways. This new study by Tadatsugu Taniguchi and colleagues in Japan reveals that the antiviral IRF3 not only leads to the production of antiviral proteins but also directly inhibits the production of the antibacterial IL-12. When they tested this phenomenon, by co-infecting mice with a virus and with sub-lethal doses of bacteria, it proved to be lethal. However, when IRF3-deficient mice were subjected to the same treatment, they recovered. This confirmed that IRF3 is needed for the suppression of antibacterial IL-12. To show that this suppression of the antibacterial pathway is caused by IRF3 itself and not a downstream product of the genes it activates, they used mice deficient for the interferons triggered by IRF3. The results showed no difference in their outcome, indicating that this phenomenon is caused specifically by IRF3.
To better understand the underlying mechanism behind the IRF3 suppression of antibacterial genes, the scientists looked into the specific mechanism behind gene activation at the point where these proteins physically interact with DNA. It is known that IRF5 needs to bind to a specific region of DNA in order to activate antibacterial genes. Using an assay that identifies regions on the DNA where a specific protein binds, the scientists found that IRF3 binds directly and blocks access to the same segment of DNA that IRF5 needs to bind to. This is akin to IRF3 parking in IRF5’s reserved spot, thereby preventing IRF5 from parking and going to work. It is important to note that when IRF3 parks in the spot for IRF5, it simply stays there and blocks the access for the designated protein but does not do the work that is assigned with that spot.
These new findings are crucial pieces of the puzzle that shed light on the dynamics of the immune system. We are constantly exposed to different types of bacteria, which would be deadly without our immune defenses. When we are eating at the school cafeteria, riding public transportation, pushing the elevator button, kissing someone goodbye — these are all instances during which we are exposed to bacteria that our antibacterial branch of the immune system fight off successfully. But these scenarios could spell trouble if the antibacterial pathway is suppressed, as is the case when we are infected with a virus.
So what could be the advantage to inhibiting our antibacterial defenses when we are infected with a virus? Millions of years of evolution have led us to this point, so there must be a purpose behind this. The authors of the study believe that by suppressing that branch of the immune system, our bodies are protected from an all-out World War-type of immune response that could be lead to excessive inflammation and likely be deadly. There are countless instances in which the immune system does more harm than good, such as with allergies or autoimmune diseases, and this type of mechanism may help protect us from exacerbated cases like these.
Based on: “Cross-interference of RLR and TLR signaling pathways modulates antibacterial T cell responses”, Nature Immunology, July 2012.
Breaking the Barrier: Can a shot in your arm deliver genes to only your brain?
By: Lindsay Johnson
As you read this article, somewhere between 0.5 and 1 million people in the United States are suffering from Parkinson’s Disease, a disorder in which motor neurons in the brain die, resulting in debilitating tremors and the inability to initiate movement (1). There is no cure for Parkinson’s, but some proteins called growth factors have been shown to help the dying motor neurons survive. While scientists found that these growth factors could treat Parkinson’s symptoms, there was a major obstacle: the barrier of blood that surrounds the brain, keeping anything but the smallest molecules outside.
One solution to this blood brain barrier is the very smallest of molecules: a virus, specifically the ninth adeno-associated virus (AAV9). Scientists can put genes for growth factors into this virus and inject it into the blood stream. Once in the blood, the virus will hone towards the brain, seep through the barrier, and deliver its treasure to the dying motor neurons. While this seemed like the perfect treatment method, one problem remained: AAV9 doesn’t just go to the brain; it also goes to the liver, skeletal muscle, and heart, building up in toxic levels. The key to treating brain diseases like Parkinson’s lies in the ability to stop these peripheral effects.
Recently, Xie et al. devised an answer to the problem (2). They realized that small RNAs called microRNAs could be used to attack and destroy the virus in the liver, muscle, and heart. microRNAs, which are different in every tissue, float about in the cell seeking out a target site; once they have found the site (usually in other RNAs), they cut and destroy the target. Xie et al. realized that they could trick microRNAs into destroying viruses by inserting the microRNA target sites into AAV9.
To test their hypothesis, Xie et al. put the viruses with the microRNA target sites into liver cells (the HuH7 cell line). They found that the viruses with the liver microRNA target were destroyed by the microRNA in the cells, but the viruses with the heart/skeletal muscle microRNA targets were not destroyed. This meant that the virus was effectively fooling the microRNA into destroying it, and it meant that the effect was due to a specific interaction between the microRNA and the target site.
To show that this treatment could work in the liver, heart, and skeletal muscle of mammals, Xie et al. injected the virus containing the tissue-specific microRNA target sites into mice. The authors found that the virus tricked the mouse microRNA into destroying it in the liver, heart, and skeletal muscle. Again, the virus was not destroyed in any other tissues, showing that the effect was specific.
These discoveries of Xie et al. have a huge impact on treatment of central nervous system (CNS) diseases. While AAV9 is the only kind of adeno-associated virus that goes straight to the brain, scientists couldn’t use it to deliver treatments because of its toxicity in other tissues in the body. Now that there is a way to inhibit these peripheral toxicities, AAV9 can be used to bring treatments for the brain. For people with Parkinson’s, this could mean a turn around in their disease; growth factors brought to the motor neurons could help them survive, preventing the damage that causes the symptoms of the disease.
This innovation is not useful only to Parkinson’s Disease. It is also useful to every brain disorder that could benefit from gene therapy, from Alzheimer’s Disease to Lou Gehrig’s Disease. Dementia, especially Alzheimer’s Disease, affects 25 million people worldwide (3). Xie et al.’s simple, effective method for delivering treatments to the brain opens up the field for Alzheimer’s research as well. AAV9 can carry any small gene to the CNS; it is not limited to the growth factors beneficial to Parkinsonian neurons.
In addition to opening up options for many diseases, Xie et al.’s discoveries have provided a revolutionary new method of drug delivery to the CNS. Whereas before gene therapy to the brain required direct injection into the skull, now life-saving genes injected in to the arm as a shot can travel to the brain. Xie et al. may have just broken the blood brain barrier.
1. The Michael Stern Parkinson's Research Foundation. (n.d.). More information on parkinson's disease. Retrieved from http://parkinsoninfo.org/more_info.asp
2. Xie et al. (2010). MicroRNA-regulated, systemically delivered rAAV9: A step closer to CNS-restricted transgene expression. The American Society of Gene & Cell Therapy.
3. Qiu, C., Kivipelto, M., & von Strauss, E. (2009). Epidemiology of alzheimer's disease: occurrence, determinants, and strategies toward intervention. Dialogues Clin Neurosci, 11(2), 111-128.
A mouse model of post-traumatic stress disorder
By: Chido Kativhu
Don Lader sat in the premier showing of the Dark Knight Rises in Colorado, unaware that the ticket he had bought in advance would also put him in line of fire. Unfortunately, for some survivors, the years ahead will be marked with debilitating memory recalls of the assault. They become trapped in that one moment, unable to sleep, eat, or concentrate. Mr Lader, on the other hand, escaped unharmed and willing to face his attacker in court.
About half the population of the world experiences a traumatic event in their lifetime. These events range from combat, violent assaults, to natural disasters. Most people, like Mr Lader, recover well, ready to reintegrate into society. Less than 10% of those who are traumatized develop post-traumatic stress disorder (PTSD). PTSD is characterized by re-living the traumatic event over and over again, avoidance of reminders of the experience, losing interest in activities that were previously enjoyable, and hyperarousal. As such, researchers are trying to understand why some people are more vulnerable to developing PTSD than others, and the mechanisms leading to symptoms of PTSD.
Since it is unethical and horrid to expose humans to trauma and study their brains to see changes that may lead to PTSD, a group led by Dr. Griebel at the Sanofi Aventis Exploratory Unit in France used mice to understand these mechanisms. Basing their observations on sleep pattern disturbances, one of the major symptoms of PTSD, they measured brain waves indicating sleep state. Because mice are active at night and sleep during the day, they recorded the sleeping patterns of mice for six hours during day time.
In order to understand both the short and long term effects of a traumatic event on sleep patterns, the researchers first shocked the mice twice in a chamber they could not escape. Predictably, day 1 after exposure to the trauma, the mice experienced fragmented sleep as a result of the stressful event. However, 1 week, 2 weeks, and 3 weeks after receiving the electric shocks, the mice still showed disturbances in sleep patterns. Basically, the mice kept waking up several times during their sleep hours. 3 weeks of disturbed sleep in mice is roughly equivalent to about 2 years of disturbed sleep in a person with a life span of 80 years.
In addition to frequently waking up, the mice also showed less rapid eye movement (REM) sleep at 14 days. REM sleep is essential for normal daily functioning.
For people with PTSD, reliving the traumatic episode is usually triggered by external factors, something in the environment that reminds them of that event. In the worst scenarios, some people are even triggered by objects that may not be related to the event in any way. To study this phenomenon in mice, the researchers introduced a foreign object in the cage while they electro-shocked the mice. From day 1 after exposure, the mice actively avoided the object in anticipation of the shock. This lasted up to 21 days. Furthermore, at 21 days the mice avoided any object they had never encountered before, mimicking the hypervigilence and anomalies in traumatic memory triggers observed in PTSD patients.
Using this mouse model, scientists can study the progression and maintenance of PTSD symptoms to figure out why some people are susceptible to the disorder while others seem protected. Also, questions about the mechanisms involved in creating PTSD symptoms can be answered. Not only will this information allow for the development of effective ways to treat the disorder, it may also lead to preventative measures.
Of course, there are limitations to this study. For one, it is difficult to relate human emotions and behavior to mice. PTSD in particular, the behavioral challenges faced by patients are complex, and vary from one individual to the next. Therefore, an animal model may not be able to capture fully and accurately the disorder as observed in humans. However, the mouse model does provide an excellent template to get a basic understanding of how PTSD symptoms develop. Furthermore, we can manipulate a mouse model in ways that would be impractical in humans.
Citation: J. Philbert, P. Pichat, S. Beeske, M. Decobert, C. Belzung, G. Griebel. Acute inescapable stress exposure induces long-term sleep disturbances and avoidance behavior: A mouse model of post-traumatic stress disorder (PTSD). Behavioral Brain Research, Vol 221, Issue 1, 149-154, 2011.
Computers help solve genetic puzzles in cancer
By: Yasin Kaymaz
Every cell has a genetic program that coordinates the activity of nearly fifteen thousand genes. Genes produce long string-like molecules called messenger RNA (mRNA), which in turn make proteins that enact the functions of the cell. Scientists refer to the activity of genes and the genetic program as the “transcriptome.” Since active genes produce messenger RNA, measuring the amounts of these RNAs in a cell helps us understand the activity levels of genes. RNA sequencing (RNA-seq) does exactly that, and has become a widely used analysis method for transcriptome studies. This method basically chops the transcriptome up into small genetic strings – tiny, manageable pieces of the whole – called “reads”. These reads then need to be matched up to where they came from in the original genome.
Mapping small reads to the reference genome is similar to a puzzle with a million pieces. Having a million pieces, you might think it impossible to solve this puzzle. However, many of the pieces fit into the same places on the main board. Therefore, this problem becomes much easier for a computer. Algorithms use the repeating pieces and similarities to build mRNA sequences, similar to using the matching patterns on the edges of puzzle pieces to recreate the whole image. In some rare cases, you might get defective pictures on your puzzle. For example, a small piece of the image might be abnormally printed, or might have swapped locations with another piece. A human eye could easily recognize the defective pieces and distinguish them from others; however, a complicated algorithm is required for a computer. A recently developed method called TopHat-Fusion enables a computer to overcome this computationally hard problem.
TopHat-Fusion was designed to discover abnormal mRNAs that include pieces from two different chromosomes. These fusion structures are generally the results of chromosomes breaking and re-joining with other chromosomes. Most of the time, these breakpoints are harmlessly located in regions of DNA that do not produce protein. Sometimes, however, breakpoints occur in the genes that code for mRNA and produce proteins. When a fusion mRNA or protein occurs, that protein may possess unusual and dangerous functions, and could lead to cancer or other diseases. That’s why it is so important to identify chromosomal breakpoints and possible fusion proteins.
This figure represents sixty reads, aligned by TopHat-Fusion, which identify a fusion product formed by the BCAS4 gene on chromosome 20 and the BCAS3 gene on chromosome 17. Each black line represents a “read;” as you can see, each read comes from only a small portion of the gene and overlaps with other reads, allowing a computer to match up the sequences and figure out how to put them in order. Reads map and align to the reference genome when they share the same sequence of bases (represented by the letters A, T, G, C). As seen on the ladder-like figure, even though all reads align together and share common sequences, half of the reads are originally from another chromosome, according to the reference genome. Here, TopHat-Fusion has reconstructed a fusion product that includes genetic material from chromosomes 20 and 17.
One of the advantages of TopHat-fusion is that it does not use nor require any information about known genes, and uses an unsupervised learning algorithm. In other words, this tool tries all possible combinations of reads without trying to recreate known genetic sequences; it doesn’t try to fit puzzle pieces where it thinks they should go. This frees it to find abnormal products like fusion mRNAs.
Recently, many algorithms that utilize Next Generation Sequencing data have provided highly precise solutions to some major biological problems such as finding chromosomal abnormalities and alterations. “FusionFinder”, “nFuse”, and “BreakFusion” are some of the attempts. However, TopHat-Fusion is an extension of the widely used RNA-seq data analysis pipeline TopHat. Therefore, it can be integrated into the pipeline much more easily when compared to the other fusion detection tools. TopHat-Fusion is an open source software and freely available from tophat.cbcb.umd.edu.
Source: Kim D and Salzberg SL. “TopHat-Fusion: an algorithm for discovery of novel fusion transcripts”. Genome Biology 2011, 12:R72
Motoring towards motor neurons for cell replacement therapy
By: Nicola Kearns
A fibroblast cell and a nerve cell don’t usually have much in common but recently Dr Eggan and collaborators at Harvard Medical School have figured how to change fibroblast cells into motor neurons.
Motor neurons allow the brain to talk to the muscles of the body, telling them when to move, enabling us to walk, run, jump and skip. The brain sends an electrical signal through a motor neuron like a message travelling down a telephone wire, letting the receiver, the muscle, hear and respond to the message. Motor neurons are made when the body is developing, before birth. Adults are not able make new motor neurons, which means that if they become damaged, the brain cannot communicate effectively with the muscles and in some cases these defects can result in paralysis. Figuring out how to make motor neurons from other cell types will help future scientists grow them in a dish, allowing scientists to replace the bad cells with good ones when motor neurons are missing or damaged such as in spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). In both SMA and ALS the motor neurons die or are destroyed over time, preventing the brain from interacting with the muscles, the muscles eventually stop working and patients become paralyzed.
Fibroblast cells on the other hand have the unrelated responsibility of making the connective tissue in the body, the tendons, cartilage, bones and fat tissues. The main job of a fibroblast cell is to produce fibers, providing structural support for other tissues.
Each type of cell in the body makes specialized proteins to help them carry out their job. Dr Eggan and colleagues found that if they added some of the specialized proteins found in motor neurons to fibroblast cells, the fibroblast cells went through a series of changes. In fact, some of them stopped being fibroblast cells altogether and instead turned into motor neurons, which the scientists named “induced motor neurons”. When the scientists compared the induced motor neuron cells to real motor neurons and real fibroblast cells, they found that the induced motor neuron cells most closely resembled real motor neurons. Not only did these cells have motor neuron specific proteins and lose their fibroblast specific proteins, they actually functioned like a motor neuron. The induced motor neurons responded to electrical signals, like the ones given by the brain. When placed on muscle cells, they made interactions with the muscle and caused the muscle cells to twitch and contract, just like the muscles in your body. The researchers then transplanted these cells into developing chick embryos and found that the induced motor neurons integrated into the nervous system and functioned correctly inside the chick.
These induced motor neurons cells could be used to help researchers study the mechanisms of specific diseases where motor neurons are damaged or destroyed. Having a population of functional motor neurons in a laboratory setting can enable testing of possible drugs or treatments for people with SMA or ALS. Since adults cannot make new motor neurons, the possibility to make them in a dish and transplant them into patients as replacements for the motor neurons destroyed or damaged by disease is a long-term goal of regenerative medicine.
The ability to make functional motor neurons safe to transplant from a person’s own fibroblast cells would have many benefits. Firstly, fibroblast cells are easier and relatively painless to obtain when compared to neurons. In addition, usually people need immunosuppressants after a transplant to prevent the body from rejecting the new tissue. However, making the cells for transplant from fibroblast cells might prevent this rejection. Since these cells already belong to the patient, the immune system would accept them, unlike cells donated from a different person. While scientists are not ready to transplant these induced motor neurons into humans just yet, the knowledge gained in learning how to turn fibroblast cells into motor neurons makes promising strides toward generating motor neurons for cell replacement therapy.
Son, E.Y., Ichida, J.K., Wainger, B.J., Toma, J.S., Rafuse, V.F., Woolf, C.J., and Eggan, K. (2011). Conversion of mouse and human fibroblasts into functional spinal motor neurons. Cell Stem Cell 9, 205–218.
Will you smoke if smoking helps you have a beautiful shape?
By: Heesun Kim
We know that smoking is harmful to our health. Cigarettes contain more than 4000 chemical compounds and about 400 toxic substances. In particular, nicotine is addictive and causes cholesterol to accumulate in the body. According to the National Cancer Institute, smoking causes cancer in various types of organs, including the throat, mouth, nasal cavity, esophagus, stomach, pancreas, kidney, bladder, and cervix, as well as acute myeloid leukemia. Furthermore, in a recent study, the researchers wrote, “it is possible that smoking promotes development of dementia or Alzheimer’s disease.” Smoking also increases the risk of heart disease.
Nevertheless, many smokers are reluctant to quit smoking because they think it makes them gain weight. Actually, some smokers experience a gain in weight when they quit smoking. Interestingly, a Science paper by Mineur and colleagues (1) reports that smoking contributes to weight loss by decreasing appetite, which shows smoking really helps you control your body weight.
Which organ is responsible for controlling metabolism in our body? You may think that the answer is the stomach, but the brain controls metabolism. The hypothalamus, a portion of the brain, controls appetite through its receptors. You feel full when the receptors get a signal to inform your brain that you already have enough energy. This signal is made in two ways: one is expansion of the stomach and the other is blood glucose levels. However, a third, non-typical way of signaling the brain is through nicotine, a major component of cigarettes. However, so far, scientists don’t know which molecule is the major target that influences appetite. Therefore, this paper is very meaningful because identifying target molecules that respond to nicotine and suppress appetite can lead to a pharmacological approach to developing an ideal drug to make us slim.
First, in this paper, Mineur and colleagues showed that nicotine decreased body weight and fat content in mice. Here, they found that certain receptors (α3β4) in the hypothalamus have a major role in decreasing food intake by binding the nicotine (Figure 1). When α3β4 receptors are removed in mice, nicotine does not affect their food intake, whereas mice with these receptors show lower food intake than the control group.
Another part of the hypothalamus shown to help in weight control a pro-opiomelanocortin (POMC) cells (Figure 1), which decrease food intake and increase consumption. Mice lacking POMC cells are known to become obese. In the Nature paper, Mineur and colleagues revealed the link between α3β4 receptors and POMC cells. Specifically, the α3β4 receptors are located on POMC cells. They found that nicotine turns on POMC cells through α3β4 receptors, which leads to decreasing food intake. If mice have no POMC cells, they have no α3β4 receptors and therefore cannot respond to nicotine. On the other hand, normal mice with POMC cells have α3β4 receptors, so nicotine decreases their food intake.
POMC cells send the signal they receive from α3β4 receptors to melanocortin 4 (MC4) receptors in another part of the hypothalamus (Figure 1). Both MC4 receptors and POMC cells play essential roles in controlling food intake and energy consumption. Therefore, Mineur and colleagues investigated whether MC4 receptors are involved in the effect of nicotine on food intake. They show that food intake in mice without MC4 receptors is not influenced by nicotine, while food intake in normal mice with MC4 receptors is decreased by nicotine.
In summary, nicotine affects α3β4 receptors, which activate POMC cells. Then, the POMC cells activated by the nicotine deliver the signal to MC4 receptors on the second-order neurons in another part of the hypothalamus (Figure 1). Eventually, the brain part that gets this signal orders our body to suppress appetite. If we can develop a drug to target these receptors or brain cells, including α3β4 receptors, POMC cells, and MC4 receptors, all people would keep in good shape without any of the harmful effects of smoking.
Smoking becomes a kind of double-edged sword as shown by the results of this study. The choice lies with you. Don’t smoke if you prefer health to appearance. If not, you can smoke. In any case, it is certain that the results of this study will hasten the date for producing an ideal drug to make us have a fantastic appearance without the negative effects of smoking.
Figure 1. Appetite-suppressant effect of nicotine in the brain (from ref 2).
1. Mineur YS et al., Science, 332(6035): 1330–1332; 2011.
2. Seeley RJ, Sandoval DA, Nature 475: 176-7; 2011
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