[♪ INTRO] You know how great TV shows often take you on a journey, with twists and turns leading to an ending you never saw coming?

Science is like that sometimes, too. Consider the case of iPSCs, a kind of stem cell researchers thought was going to revolutionize cellular therapy.

After years of clinical trials, that failed to happen. But, as luck would have it, iPSCs ended up advancing completely different fields. First, a little background: Each cell in your body is optimized to perform a highly specialized role.

Your neurons have long, thin structures called axons to carry electrical signals. Your red blood cells don’t contain a nucleus so they have more room to carry oxygen. Each cell also began as exactly the same thing: a humble stem cell with the potential to become anything.

We used to think that once a stem cell had become specialized (a process called differentiation) that was how it was stuck forever. But a surprising discovery in 2006 by Japanese biologist Dr. Shinya Yamanaka changed that.

His team used modified viruses to deliver 24 genes into adult skin cells. When the viruses entered the cells, they hijacked the cellular machinery and inserted their DNA into the host DNA. When these cells were left to grow, they became something else entirely.

They now looked and behaved just like the stem cells found in embryos. The team tested combinations of the 24 genes until they were left with just 4 that were necessary for the reversal of an adult cell back to a stem cell. Those 4 genes created a type of protein that controlled if and how much of other genes were expressed.

They changed the genes expressed in an adult skin cell into something very similar to an embryonic stem cell. The researchers called these incredible new cells: induced pluripotent stem cells, or iPSCs. Pluripotency means the ability to turn into almost any other type of cell. iPSCs were immediately seen as a major breakthrough in stem cell biology, and researchers believed they had incredible medical potential.

Just imagine: an unlimited supply of a specific cell types to repair an organ or tissue that wouldn’t be rejected by the patient’s immune system because they came from the patient! And to top it all off, iPSCs could be made without the tricky ethical issues that come with using stem cells from embryos, which had been the basis for much stem cell research up to that point. The first clinical trial kicked off in 2013, with researchers making iPSCs from the skin cells of patients with macular degeneration, a condition where damage to the retina leads to loss of vision.

The iPSCs were differentiated into retinal cells and transplanted into the eye of the first patient, whose vision improved! But the excitement that had been building over these cells was short-lived. The iPSCs generated from the second patient showed unexpected mutations.

Due to safety concerns, the trial was immediately halted. Now, that initial failure wasn't all that surprising, considering that it can take decades before a scientific breakthrough results in something that people can actually use. But in the 16 years since IPSCs were discovered, there has been little progress on that front.

Changing enough adult cells into iPSCs for cellular therapy turned out to be difficult. And genetic mutations have been a problem in subsequent trials. As of 2021, only 19 clinical trials have taken place that transplanted iPSCs into patients for therapeutic reasons.

Of those, only one has advanced to the final phase of testing. But that’s not the end of our story. Although research into the use of iPSCs for cell therapies stalled, they would soon lead to incredible advances in other areas.

In those applications, the potential for genetic mutations or the technical difficulties of producing enough cells for use on humans weren’t a problem. As we mentioned, iPSCs are very similar to embryonic stem cells. This has allowed researchers to create embryo-like structures that mimic the early stages of human development about 2 weeks after an embryo has been implanted into the uterus.

These structures are organized into the three layers of different cell types that give rise to tissues and organs. They can be used to study the incredibly complex biological processes of early development like organ formation and the development of the nervous system. Hopefully, this will help us understand why things go wrong during that stage of development, like heart defects that are present from birth.

Until iPSCs came along, we weren’t able to study things like that due to an international policy that says embryos can’t be used for research more than 14 days after fertilization. And it doesn’t stop there. iPSCs can also be used to study diseases in a dish. Take Parkinson’s, for example.

By the time it’s diagnosed, most of the patient’s dopamine-releasing neurons in a critical area of the brain called the substantia nigra are already lost. Researchers have made iPSCs from the skin and blood cells of patients with Parkinson’s using similar methods to those we described earlier. This has allowed them to grow an abundant supply of that kind of neuron, study why they’re dying, and even test potential new drugs on those cells before moving into clinical trials.

In the future, this might lead to more personalized medicine, where your iPSCs are used to test what treatment works best for you. iPSCs are even on their way to tackling organ donor shortages. Cells generated from mice have been inserted into rat embryos which were genetically edited so the rat could no longer grow a pancreas. The mouse iPSCs filled the empty niche, growing into a pancreas.

In theory, we can use the same technique to grow human organs in animals like pigs. But we’re not quite there yet. Human iPSCs have been successfully incorporated into pig embryos before, but in small numbers.

So there are a few more kinks to iron out before we can grow a full, custom organ. In 2012, Shinya Yamanaka won the Nobel Prize in Physiology or Medicine for his discovery of iPSCs. At the time, iPSCs were promised as the future of cell therapies.

But their true value was unexpected. They’ve changed how scientists approach many other aspects of biological research forever. Like that TV show with the wicked twist, iPSCs have delivered a satisfying ending no one could have predicted.

I can’t wait for season 2. I also can’t wait for this month’s SciShow Space pin! And you shouldn’t wait, because it’s going away at the end of the month and will never come back.

The November pin features NEAR Shoemaker, a NASA mission designed to meet up with an asteroid near Earth. And when this pin is no longer available at the end of the month, there will be another one for you, specially made for December. What do you do with these pins, you ask?

Put them on your fancy new pin board! You can find the pin and pin board at DFTBA.com/SciShow and the link in the description down below. They come separately or bundled!

Thanks for taking a look! [♪ OUTRO]