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Sometimes, studying uncommon maladies can reveal larger insights into how our bodies work!

Hosted by: Hank Green

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Sources:
https://rarediseases.info.nih.gov/diseases/pages/31/faqs-about-rare-diseases
https://irp.nih.gov/blog/post/2015/06/top-5-reasons-to-study-rare-and-undiagnosed-diseases

Osteo
https://www.thebonejournal.com/article/S8756-3282(11)00969-0/fulltext
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5069370/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC292015/pdf/jcinvest00194-0009.pdf
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5726215/

Gaucher
https://www.sciencedirect.com/science/article/pii/S0896627317300429
https://rarediseases.org/rare-diseases/gaucher-disease/

Niemann-Pick
https://rarediseases.org/rare-diseases/niemann-pick-disease-type-c/
https://www.nature.com/articles/nature10348
http://www.pbs.org/wgbh/nova/next/body/the-rare-disease-thats-helping-researchers-cure-ebola/
https://www.nature.com/articles/nature10380

Leptin
https://www.nature.com/articles/43185
https://www.nejm.org/doi/full/10.1056/nejmoa1406653
http://www.laskerfoundation.org/media/filer_public/82/b6/82b68546-b467-4410-a08c-a91458740306/2010_b_coleman.pdf
https://www.jax.org/strain/000632
https://ghr.nlm.nih.gov/condition/congenital-leptin-deficiency

Laron
http://discovermagazine.com/2013/april/19-double-edged-genes
https://www.nbcnews.com/health/aging/little-people-ecuador-laron-syndrome-may-unlock-cancer-diabetes-cure-n511266
https://rarediseases.info.nih.gov/diseases/6859/laron-syndrome
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4531065/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3943600/

plasminogen
http://www.sciencemag.org/news/2017/11/mutation-blood-clotting-gene-may-extend-human-life-span
http://advances.sciencemag.org/content/3/11/eaao1617
https://rarediseases.info.nih.gov/diseases/4381/plasminogen-activator-inhibitor-type-1-deficiency

Images:
https://commons.wikimedia.org/wiki/File:XrayRicketsLegssmall.jpg
https://commons.wikimedia.org/wiki/File:1ALK.png
https://commons.wikimedia.org/wiki/File:Pyrophosphate-3D-balls.png
https://commons.wikimedia.org/wiki/File:Osteoporosis_Locations.png
https://commons.wikimedia.org/wiki/File:Bisphosphonate_structure.jpg
https://commons.wikimedia.org/wiki/File:Osteoclast.jpg
https://commons.wikimedia.org/wiki/File:Animal_Cell.svg
https://commons.wikimedia.org/wiki/File:Structure_of_human_beta-glucocerebrosidase_@.png
https://commons.wikimedia.org/wiki/File:Protein_NPC1_PDB_3GKH.png
https://commons.wikimedia.org/wiki/File:Ebola_virus_virion.jpg
https://commons.wikimedia.org/wiki/File:Niemann_pick_cell_in_spleen.jpg
https://commons.wikimedia.org/wiki/File:Fatmouse.jpg
https://commons.wikimedia.org/wiki/File:Somatotropine.GIF
https://commons.wikimedia.org/wiki/File:Endocrine_growth_regulation.svg
https://commons.wikimedia.org/wiki/File:1OC0.png
https://commons.wikimedia.org/wiki/File:Amish_School_near_Rebersburg_PA.jpg
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Individually, rare diseases are... rare. In the US, we usually say that a disease is rare when it affects fewer than 200,000 people in the whole country. And in the EU, a disease is rare when it affects fewer than one out of every 2000 people.

That’s not very often. But because there are so many different rare diseases experts estimate there are about 7000 collectively, it’s not so rare to have a rare disease. In fact, about 30 million Americans have a rare disease, around the same number who have type 2 diabetes!

So, studying them is important in it’s own right. But these sorts of investigations can also reveal larger insights into how our bodies work. And because many rare diseases are caused by relatively simple, known mechanisms, they can also tell us about the things that can go wrong in much more common diseases.

Sometimes, this even means researchers can come up with a drug that works for millions of people. Here are six times research into the most uncommon maladies on the planet have turned out the benefit the masses. First up, a bone mineralization disorder called hypophosphatasia, or HPP.

In severe cases, which affect about one in every 100,000 people, patients have soft bones that can easily break and deform. Many patients are in chronic pain and often lose teeth prematurely, and a quarter experience more than 10 fractures in their lifetime. The disease is caused by a gene mutation that prevents the body from making correct versions of the enzyme alkaline phosphatase.

In the mid-1960s, researchers learned that this enzyme regulates the body’s production of a molecule called pyrophosphate. It’s found in blood and urine and prevents the main mineral in our bones from growing. Without enough of the enzyme, the body has too much pyrophosphate, so mineralization doesn’t happen as well.

While researchers were working to understand HPP, they realized that pyrophosphate might actually have another use, too. Previously, they’d found that this molecule had a perk:. It kept bone minerals from dissolving.

So maybe it could help patients with osteoporosis, a disease of low bone mass that affects 200 million people around the world. Scientists then searched for compounds that mimicked pyrophosphate, and they found that the water softening molecule bisphosphonate did the trick. Now, it’s a common osteoporosis drug although they later realized this treatment actually works for a different reason:.

It prevents cells called osteoclasts from breaking down bone. Because they don’t need extra pyrophosphate, artificial or otherwise, the drug that HPP patients helped give the world won’t help them and might even make them worse. But if nothing else, it did change how much we know about bone biology and led to a whole new class of drugs for millions of people.

Next is Gaucher disease, which affects somewhere around one in every 50,000 or 100,000 people and shares some interesting parallels to Parkinson’s. Guacher is what’s known as a lysosomal storage disease, which means there’s a defect in the organelle in cells (lysosomes) that digests garbage. When that happens, the lysosomes can’t get rid of the trash fast enough, and it builds up.

In Gaucher, this is the result of an enzyme deficiency, specifically one called glucocerebrosidase. It specializes in breaking down certain glycolipids, which are basically fats with a sugar attached to them. So without enough of the enzyme, they build up, especially in the liver, spleen, and bone marrow, which produces blood cells.

As a result, people with the disease often don’t have enough blood cells, which can make them tired and more prone to bruising and bleeding. They can also get enlarged spleens and livers. On rare occasions, Gaucher patients also develop symptoms ike tremors and slow movements similar to Parkinson’s, a neurodegenerative disorder that famously affects people’s ability to move.

Initially, scientists didn’t make much of this. Then, they noticed something surprising with the relatives of Gaucher patients. Those who carried the mutation that causes the enzyme deficiency were more likely to get Parkinson’s, too.

In fact, a huge genetic study in 2009 revealed that around 7% of participants with Parkinson’s had a mutation in that gene the most for any single gene. In genetics, a finding like that for a multi-factorial disease like Parkinson’s is huge. Now, scientists are working to figure out what it means.

One possibility is that not having enough of that enzyme prevents cells from breaking down alpha-synuclein proteins. These can get misfolded in the brain and are thought to be one of the main causes of Parkinson’s. That’s unlikely to be the whole story, but it could be important for a subset of cases.

Scientists are hopeful that studying this enzyme and lysosomes in general may lead to a new understanding of Parkinson’s, and possibly to new treatments for the disease, and for those with Gaucher, too. But the fact that Gaucher has already helped identify the biggest genetic risk factor to the second-most common neurodegenerative disease is a pretty big deal. Speaking of lysosomal storage diseases as you do scientists are finding that another one, called Niemann-Pick, might help us combat Ebola virus.

Technically, and fortunately, Ebola hemorrhagic fever is also a rare disease. But that could change at any time with an outbreak. Back in 2011, researchers were studying the virus to figure out how it was getting into cells.

They knew it used a certain glycoprotein to do it, but they didn’t know what on our cells it was targeting. So, they set up a screen, testing the Ebola glycoprotein on a series of different cells, each of which had one mutation. Weirdly, a bunch of the cells that kept the virus out had a mutation in a gene called NPC1, which makes a protein that helps shuttle cholesterol around inside cells.

This is the same gene that’s mutated in Niemann-Pick disease type C, or NPC, which affects around one in 150,000 people. Patients with it end up with build-ups of cholesterol inside neurons, which can cause dementia at a shockingly early age. For that reason, it’s sometimes called ‘childhood Alzheimer's.’ Thankfully, there are some treatments for it, but the disease itself could also help treat thousands of others.

Because when scientists tried to infect cells from NPC patients with Ebola… they couldn’t. The mutation was keeping Ebola out. The fact that Ebola targets NPC1 explains part of why it’s so deadly it’s in all cells, so the virus can target any cell of the body, not just a few like most viruses.

Now, researchers are using this knowledge to create new Ebola drugs. If they can make molecules that block the NPC1 protein, they may be able to prevent people from getting infected. Sometimes, rare diseases are helpful to scientists because they can confirm that what they’ve seen in lab animals also applies to humans.

That’s what happened with an extremely rare condition called congenital leptin deficiency. As the name implies, people with the disease don’t make enough leptin, a hormone that fat cells produce to tell the body to stop eating. As a result, they’re constantly hungry and eat way too much food.

These people become obese very early in life, usually within months of being born. We know of about 30 cases now, but for a long time, we didn’t know the condition existed. And that became important because for decades, scientists have been using a mouse with mutations in its leptin genes to study type 2 diabetes.

The mice become very obese, and if they have the right genetic background, they develop diabetes quickly, making it easier to study the disease in the lab. Years of mice experiments suggested that leptin might be important for our understanding of obesity. But no one was really sure how relevant it was to people.

That changed in 1997, when researchers identified two severely obese children who shared the same mutation in their leptin genes. They made far less leptin than normal, showing that this hormone was a key player in how our bodies regulate the amount of food we eat and how much fat we put on. Like with Niemman-Pick and Ebola, some rare diseases, it turns out, come with perks.

In the case of something called Laron syndrome, those advantages are potentially life-changing for the rest of us if we can figure out how to mimic them. People with Laron’s are very short under 1.4 meters tall because of a mutant growth hormone receptor. Even though they make plenty of growth hormone, their bodies can’t use it normally, so they never get very tall and their limbs are short.

It’s a unique form of dwarfism, and fewer than 400 cases have been diagnosed worldwide. The surprising thing is, even though these people are often obese, they have normal blood pressure, and they seem impervious diabetes and cancer. In one village in Ecuador where the condition is common, just one person in a sample of 99 was diagnosed with cancer.

In contrast, cancer kills about 20% of the relatives of people with Laron syndrome. The secret, both to their disease and their superpowers, may have to do with something called insulin-like growth factor 1, or IGF-1. For those with Laron’s, growth hormone receptors don’t trigger cells to make IGF-1.

And since that’s what tells the body to grow, not having it around explains their short stature. But IGF-1 is also thought to contribute to uncontrolled growth in some cancers, so limiting it in adults might be a good idea. So far, scientists have even found that mice missing the growth hormone receptors make less IGF-1 and live longer and are less diseased.

Now, they’re working on ways to get the same results with a pill or supplement. Finally, if going cancer and diabetes-free isn’t enough, there’s a rare blood clotting disease that’s revealing a lot about aging, too. In plasminogen activator inhibitor type 1 deficiency, patients lack a specific blood clotting protein, so clots break down faster than they should.

Which obviously isn’t great. But last year, scientists studying an Amish community in Indiana, where the condition is more common, found that carriers of the disease live abnormally long, around 10 years longer than their peers. They also have fewer cases of diabetes.

These carriers make less of the protein than normal, but fortunately don’t have any problems with clotting. It’s still preliminary, but researchers in Japan are now testing a therapy that partially blocks the clotting protein. If it works, it could be an amazing outcome of studying something that affects just a few hundred people.

Digging into rare diseases doesn’t seem to make a lot of sense if you’re trying to do the most good for the most people. But as these examples show, because of our shared biology, it’s often remarkable what we can learn. It’s been the spark behind osteoporosis drugs, a key part of our understanding of Parkinson’s, and might even let us live longer, healthier lives.

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