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?