Thursday, February 28, 2013

No Pain, A Lot of Gain! Rare Disease Day 2013

Official Promo Video of Rare Disease Day 2013

Today is 2013's International Rare Disease Day and events are taking place in recognition of this day across the world. If you'd like to read more about the events associated with this today's celebration, click here. Most people who read this might ask themselves, "What exactly constitutes a 'rare disease'?" and, "Why is this an important research field when there is a budget crisis?"

Interestingly, a rare disease is defined based on what country you are in. For example, in the United States a rare disease is defined as a disease that affects less than 200,000 people. But, in the European Union, a rare disease is one that affects 1 in 2000 people. According to the website linked above, there are approximately 6,000-8,000 of these rare disease worldwide and unfortunately for these patients, very little is known about these conditions. In an era where scientific funding is being increasingly scrutinized, it may seem difficult to justify research into these rare diseases. But, my hope is that by the end of this post, I may have given you some small insight into why this is important.

Not all of the rare diseases are caused by genetic mutations but these rare genetic diseases can give us vital insight into biological processes. I think a great example of this is a disease that I think is quite possibly the most interesting rare disease: Hereditary Sensory and Autonomic Neuropathy Type IV (HSAN IV) or Congenital Insensitivity to Pain with Anhidrosis (CIPA). I was first introduced to this disorder during the episode of House, M.D. entitled, "Insensitive." The beginning of the episode features a young girl who after arguing with her Mother in the car, gets into a car accident and has shrapnel embedded into her leg but is completely unfazed by this! Popular culture aside, this is an accurate description of what happens to CIPA patients when they are injured: no pain.

No pain sounds great, right? Wrong! Although being pain free sounds wonderful, pain is actually a good thing. Think of a young child accidentally touching a hot stove. That kid will certainly learn that the stove is hot, the high heat burns, and they probably will not be doing this again any time soon. Well, unless they are insane (according to Einstein: Insanity = doing the same thing twice and expecting different results). As babies, CIPA patients do not have the feedback of pain and therefore develop certain compulsions that other babies wouldn't. For example, CIPA patients typically have severe scarring around their mouths because as babies, they compulsively chew on their lips and have no reason to stop. As you can imagine, these patients are highly prone to infections because, a majority of the time, they are unaware of injuries. The other part of the disease name, 'Anhidrosis' refers to another feature of this disease, the inability to sweat. I personally wish I could turn off my ability to sweat during the sweltering summers of D.C. CIPA patients routinely develop high-grade fevers because they are unable to expend heat through sweating (this having to do with a failure of the sympathetic nervous system to innervate or connect to sweat glands during development). In addition to routine infections, these severe fevers can be deadly for these patients. This disease can actually severely restrict the day to day activities of these patients but there are probably only several hundred people alive right now with this rare disease. So how can we justify spending resources into researching a disease such as CIPA?

Rare disease research is extremely important. Not only will researching these diseases facilitate treatment for these patients, but the information we gain about basic biology is extremely important. In the case of CIPA, the cause remained largely unknown until the completion of the Human Genome Project. The availability of the human genome allowed researchers to conduct a screen to determine what genes might be mutated in these patients and found a strong candidate. It turns out that neurotropic tyrosine kinase receptor type 1 (or NTRK1) was mutated in these patients. But, how does a mutation in this gene result in such serious side effects? To begin answering this question, mice were generated which lack NTRK1 and researchers found that these mice do not respond to any noxious stimuli. This suggests that this receptor is extremely important for healthy development. NTRK1 binds a protein called nerve growth factor (or NGF; a growth factor that was so important that research into it resulted in the 1986 Nobel prize in Physiology of Medicine awarded to Rita Levi-Montalcini and Stanley Cohen. If you are not familiar with Rita Levi-Montalcini, she is probably one of the most inspiring stories of dedication to science as she hid from Nazis during World War II in order to continue her experiments. Read about her.). NGF is critically involved in making sure neurons survive during development. And as you can imagine, stimulating NTRK1 with NGF during development is important in order for neurons that sense pain to survive. But, when NTRK1 is mutated in the case of CIPA, these important neurons fail to divide, differentiate and subsequently die. One of the most remarkable clinical features of this disease is that these patients lack a region of the spinal cord called, "Lissauer's Tract." This part of the spinal cord normally carries information on pain and temperature. This means, that due to the mutation in NTRK1, neurons that are required for detecting pain never develop and results in the physical inability to sense pain!

I titled this post, 'No Pain, A Lot of Gain!' because this is one of the many examples of how some rare disease results in biologists collecting a wealth of information that not only will help guide the treatment of these patients because we now understand the disease. This information also helps us in understanding–in this case–how our nervous system develops and how we develop complex sensations like pain and temperature. If say, during other disease processes, pain and temperature detection becomes disrupted, we now have a great idea of where to start when investigating the problem.

I hope you all take some time to understand the importance of the international Rare Disease Day this February 28th and recognize the importance of funding research. To get you started, here is a link to the Wikipedia entry about CIPA. What rare disease do you think should be actively researched?


Friday, February 22, 2013

Neuroscience from Okinawa!

Hey All! The last few months have been insane. Holiday craziness, a brief–but hectic–return to research followed by a two week long workshop on molecular neuroanatomy in Okinawa resulted in an action packed start to 2013. When debating on how to kick off blogging in 2013, I thought it mandatory to start off with what was one of the most fruitful scientific excursions of my career thus far: a course on molecular neuroanatomy hosted at the Seaside House of the Okinawa Institute of Science and Technology (or OIST). Located on the subtropical island of Okinawa, this research institute–and now university–is creating a community that enthusiastically encourages an international scientific community. Anyone who is interested in science would love to hear about what this university is doing and you can do exactly that in this near 8 minute featurette available on the university's YouTube channel: "Science Without Boundaries."

What better setting could there be for an intensive course in molecular neuroanatomy? Still don't believe me? Here are a few photos I took during my two week adventure.

One of the many beautiful views of the coral reefs from the OIST Seaside House

One of my favorite photos taken on the trip from when the group toured the ruins of Nakijin Castle.

A stunning shot of one of the whale sharks in the tank of the world's third largest aquarium at Churaumi Aquarium. Some people may be familiar with this somewhat famous YouTube video that is now approaching 10 million views of this ginormous tank that holds close to 2 million gallons of water! Are you inquisitive and thinking, "Well, what is the world's largest aquarium? I'll go look it up." Don't fret, I have that information for you; it is the Georgia Aquarium in Atlanta, Georgia and contains 8 million gallons of water in the tanks.

Well, this IS a neuroscience blog and not a travel website but hosting a workshop in the wondrous location of Okinawa, Japan was highly distracting, as you can no doubt see in these pictures. 

The workshop was also co-hosted by the Allen Institute for Brain Science and was a project-oriented course. Half of our time was spent during the work day attempting to consume masterfully presented neuroanatomical knowledge. I say that because we had the auspicious opportunity of having our formal lectures taught by world renowned neuroscientists such as Charles Watson, Luis Puelles, George Paxinos, John Rubenstein, Gordon Arbuthnott, and Erik De Schutter. If you work on the brain at all, then you're probably familiar with the staple in most neuroscience labs: The Paxinos and Watson Brain Atlases. We covered an overwhelming amount of information in these lectures but I found the comparative neuroanatomy to be the most useful. As a researcher who exclusively works on rats, training on neuroanatomy that does not involve the human brain is often lost in a lot of coursework (especially when Ph.D. degrees are granted under a medical school) and was much appreciated!

The other half of our days were spent being intensively trained on the Allen Institute's resources which can be found here. If you are unfamiliar with their resources, browse their website and watch tutorials for atlases that are useful for your research! We were assigned group and individual projects during the workshop and the results presented by the groups and individuals were impressive. Training and information provided by John Hohmann, Terri Gilbert, Josh Royall, and Chris Lau of the Allen Institute were invaluable and guided our work for our projects. For my individual project, I opted to semi-quantitate the expression of a group of genes throughout development that are strongly involved in the development of seizures. What began as a training exercise is now something I am going to be including in an upcoming publication from our lab. The great thing about the data is that we now think we'll be able to submit the paper to a much higher impact journal. Huzzah!!!

Numerous resources are available from the Allen Institute, but probably one of the most impressive to look at is the new Mouse Connectivity Atlas. This atlas gives neuroscientists the ability to see how a particular brain region is connected to another. Why is this important? Well, an apt/hilarious expression we heard during the workshop is that, "The brain is not a sack of potatoes." What this means is that separate brain regions, which are associated with particular functions do not act independently of one another. So, in order to fully understand your research, you must understand the highly intricate connections that your brain region of interest shares with other brain structures. Our lab is very interested in the basolateral amygdala, but how does this very important structure connect with other parts of the brain? Below you can find a short video (sorry for the low-resolution) from Allen's resources that demonstrates the important connections of this structure:

WOW! Is that not cool or what? I feel like you don't even need to really have a huge interest in neuroscience (although I hope you have some interest since you're reading this!) to appreciate how impressive the results are when you trace connections in the brain starting at the basolateral amygdala. In our lab's experimental model of epilepsy, there is very strong evidence that seizures are generated from the basolateral amygdala, and from this video, there is a very simple observation that can be made: it is quite obvious why seizures generated here can spread easily to the entire forebrain. The great thing about these resources is that there is a dearth of data freely available and can be used for publications to answer sophisticated questions. I highly encourage anyone interested in the brain to take a look at their resources and for neuroscientists, becoming familiar with these tools will greatly strengthen your knowledge on the molecular neuroanatomy of the brain and can facilitate high impact publications. 

More neuroscience to come soon from our nation's capital.