Thanks to Brilliant for  supporting this SciShow video!

As a SciShow viewer, you can keep  building your STEM skills with a 30 day free trial and 20% off an annual premium  subscription at Brilliant.org/SciShow. “You can have too much of a  good thing” is age-old wisdom that applies to a lot of things: too much  ice cream might give you a stomachache and too much matter in one tiny  space might give you a black hole. And this principle can also apply to vitamin D.

If kids don’t get enough vitamin D,  their bones won’t develop normally, and they’ll get a disease called rickets. But when countries started adding a  lot of vitamin D to children’s food to try to prevent rickets,  doctors learned that some kids also got sick from having too much vitamin D. And figuring out why those  kids got sick took decades.

And researchers had to solve  the same problem twice. [♪ INTRO] Getting to the bottom of this medical  mystery is the second time that a vitamin-D related illness has  changed our understanding of disease. But let’s start with the first: rickets. The oldest known descriptions of  rickets come from 17th-century England.

The disease is probably much older,  but the Industrial Revolution brought about changes that  made children more susceptible. Rickets often caused symptoms  like delayed motor skills, chronic pain, bowed legs, and flared wrists. Fatal seizures and heart  problems could also occur.

By the turn of the 20th century,  scientists were after a cure. The study of nutrition on a  molecular level was just beginning, and researchers knew that certain  substances, dubbed vitamins, could cause problems if they  were absent from your diet. So they went looking for one involved in rickets, which led to the discovery of vitamin D.

Unlike vitamins A, B, and C,  which had already been discovered, they found that vitamin D  was a little bit different. It could come from food, sure. Cod liver oil is a good source.

But they also knew that sunlight could  cause the body to make vitamin D. Yet just knowing the cause  wasn’t enough to actually get a balanced diet into people’s bellies,  or score them beach vacations. So putting vitamin D directly  into infant formula seemed like a great way to solve a huge,  widespread public health problem.

But they might have gone a little overboard. By the 1950s in Britain, fortification  of infant formula and milk led to infants getting up to 4,000  international units of vitamin D per day. For comparison, the US Centers for  Disease Control and Prevention today recommends just 400 IU of vitamin D  per day for infants under 1 year old, and 600 IU for kids between 1 and 2 years old.

So 4,000 IU was wildly out of  proportion with kids’ actual needs. And between 1953 and 1955, Great  Britain had 204 cases of infants with dangerously high levels of calcium  that they couldn’t quite explain, beyond the associated  increase in vitamin D in food. Vitamin D helps the body  create mineralized calcium, which you need for bones and stuff.

With so much extra vitamin D in their system, and no quick way for the body to get rid  of it, too much calcium and phosphate get absorbed into the bloodstream, which leads to kidney problems and a host of other issues. New regulations limited the amount of  vitamin D that could go into fortified food, and that reduced the number of cases. But it took another 50 years  for researchers to understand who was susceptible, and why.

In 2011, researchers identified a  mutation in a gene called CYP24A1. A mutation in that gene stops the body from breaking down excess vitamin  D like it normally would. And that led to those individuals  being way more susceptible to the kidney issues that  result from too much vitamin D.

So that explains why trying to  cure one disease causes another. Mystery solved. Well… maybe mystery 90% solved.

Further research showed that, of  people with infant hypercalcemia, about 10% don’t actually have that mutation. And for a disease to be caused by a  single, clear-cut genetic mutation most of the time doesn’t make a lot of sense, because where’s it coming from if it’s  not coming from literally this one gene? To understand that, it helps  to understand what a gene is.

Genes are instructions for making proteins. And proteins do everything in your body. They pull your muscles, break down  your food, and allow neurons to fire.

They’re so important that the DNA that  doesn’t code directly for proteins has historically been ignored as “junk DNA.” After all, when there’s an error  in the instructions for a protein, it’s obvious how that can lead to disease. If the instructions are wrong, the  protein is wrong, and it won’t work. If the error is somewhere else, meh.

But about ninety-eight percent of your  genome does not code for proteins. And it’s not just there for decoration. For example, there are flags in the code on either side of every gene that  mark the beginning and end.

When a gene gets read to be turned into a protein, those flags get read as well. The resulting “message” is a  molecule called messenger RNA. And the flag on one end, the 3’ end, affects the shape of the  RNA molecule that’s created. “Three prime” is just the name for the  far end of a length of nucleic acid, such as RNA, and it’s named  that for chemistry reasons that we’re not gonna get into.

The 3’ flag of this messenger RNA is the part that seems to matter to the remaining  10% of people with hypercalcemia. Think of a properly-folded messenger  RNA like the best paper airplane, designed for that perfect loop-de-loop path. In this case, the path it  travels will take its message to the part of the cell where  it can be turned into a protein.

The 3’ end holds the message  in place while it’s being read. When the 3’ end is mutated,  the folds get all thrown off, and the plane, or the mRNA,  can’t do what it needs to do. Researchers think there are  two possible explanations: either the mRNA has trouble  moving through the cell, or once it reaches the protein-making  machinery, it just can’t hold still.

So the proteins come out with the wrong  shape, or even in just the wrong place, which means they’re not as good at their job: regulating the level of vitamin D in your blood. When researchers analyzed blood  samples from 6 patients with unexplained hypercalcemia, they found a lot of misfolded mRNA, among other things. The paper, published in 2023, showed that,  in these patients, the protein-coding part of the CYP24A1 gene was fine, so  the diagnostic tests had missed them.

But mutations in the 3’ end of the  gene meant that the mRNA was misfolded, and the protein couldn’t do its job. While it’s not the first time we’ve  ever discovered that a mutation in a non-coding region is  directly connected to a disease, it’s still pretty early for this kind of research. It’s a demonstration that that 98% of DNA that doesn’t get turned into protein really,  directly matters in people’s lives.

And that’s just how wild and  winding the path of research can be: the study of one disease led to its  cure, which led to the discovery of a new disease, which led us  to an entirely new framework to think about genetic diseases. And we owe it all to rickets, so thanks, I guess? But now that you’ve gotten  a bit of science history, you can head over to Brilliant.org/SciShow  for a Math History course.

Brilliant is an interactive online  learning platform with thousands of lessons to choose from in math,  science, and computer science. In this eight lesson course, you’ll  learn about the challenges that a dozen of the most famous mathematicians  have faced in their efforts to figure out imaginary numbers,  radicals, quadratic equations, and other fundamentals of math today. And Brilliant goes beyond  learning what a radical is and teaches you about the lives and  research that brought us that knowledge.

To dive into those stories,  go to Brilliant.org/SciShow. That search will start you  off with a free 30 day trial and 20% off an annual premium  Brilliant subscription. And thanks to Brilliant for supporting this video! [♪ OUTRO]