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  • [♩ INTRO]

  • 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.

  • So, so far, our knowledge about these rare conditions

  • looks like it's giving back many times over.

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