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Lots of genetic diseases come down to a small change in a single gene, but how do you treat those diseases when the cells involved don’t have any DNA?

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This episode of SciShow is brought to you by the American Society of Gene and Cell Therapy. [♩INTRO].

Lots of genetic diseases come down to a small change to a single gene. So you’d think that with genetic engineering, we’d be able to treat or even cure these diseases, an idea known as gene therapy.

The concept has a lot of potential, and there are already a few successful treatments on the market, including one for an inherited disease. But modifying genetic code also carries a lot of risks, so it’s been slow going. And what happened, and is still happening, with treatments for sickle cell disease is a good example of both the challenges that come from gene therapy and the unexpectedly helpful discoveries that can come from addressing them.

Sickle cell disease is the most common inherited blood disorder, with more than 100,000 patients in the US alone. People with sickle cell have red blood cells shaped like crescents, or sickles, which would be enough of a problem on its own. But their red blood cells also don’t carry oxygen as well as the usual round ones.

The symptoms range from fatigue and jaundice to bouts of excruciating pain when the curved cells jam up blood vessels. In 1949, doctors realized the shape and problems with carrying oxygen are caused by a structural change to hemoglobin, the molecule that carries oxygen around in human blood. It wasn’t long before scientists had traced the variation to specific changes to hemoglobin genes, especially in the gene for beta-globin, one of the main protein parts of the hemoglobin molecule.

But despite decades of work, we still don’t have an approved gene therapy for sickle cell disease. Red blood cells don’t contain DNA and are only alive for about 4 months before they’re broken down and recycled by the body, so to fix red blood cells, you need to fix the cells that produce them: stem cells that live in bone marrow. Researchers are working on a few different approaches to this.

The first method is simply adding working beta-globin genes to bone marrow cells. The red blood cells still carry some of the problematic proteins; they just also have enough healthy protein to reduce the degree of sickling and improve symptoms. It’s the most straightforward treatment, and there have already been multiple human clinical trials.

But it relies on repurposed viruses, modified to make sure they can’t cause disease, to insert the desired DNA into the cells, which has turned out to be tricky. A lot of viruses can’t infect bone marrow cells, so scientists developed the technique using a type known as lentiviruses. Unfortunately, these viruses can put their DNA in lots of places, which means the inserted genes can accidentally turn on or off other important genes, including ones involved in regulating cancers.

And in the early 2000s, a ten-patient trial to fix an inherited immune disorder had to be stopped early when two of the ten patients developed leukemia. The researchers figured out what caused it and were able to treat both cases, but newer designs are a lot safer. The viral genes have been stripped to only ones absolutely essential for inserting DNA, so there are fewer genes around that might make them more likely to insert the genes where they don’t belong.

Plus, the viruses self-destruct after they do their job to make sure they don’t accidentally start replicating and causing problems, like the viruses they’re based on. There are still some concerns about effectiveness and side effects, though, for example, it’s hard to be completely, 100% sure that the place where you put the extra DNA won’t interfere with the cell’s genome in a way that could lead to cancer. That’s why other researchers are trying to edit the cell’s beta-globin gene directly, replacing the disease-causing DNA with a working sequence.

Editing a gene rather than adding a new one tends to be very effective, but without the same risk of side effects because you know exactly where the new information is going, where the old one was. You’re not trying to find somewhere to stick in a new one. In one 2016 study, for example, researchers successfully edited the beta-globin genes in 90% of the human marrow cells they tested.

But when they moved on to animal trials, only 10% of cells actually survived and were incorporated into bone marrow. So, something about the editing process either makes the cells less viable, or the immune system recognizes the foreign DNA somehow and kills them off. Researchers are working out these kinks, though, and this kind of editing technique is close to ready for human trials.

But there’s another way to treat sickle cell with gene editing, and it might be the one that ultimately wins the race: getting cells to express a different protein they already have. During fetal development, we don’t actually make hemoglobin using beta-globin. We use a different protein, called gamma-globin, instead.

And the gene for it never goes away, it just gets turned off shortly after birth by regulatory genes, which tell the cell to produce beta-globin instead. Doctors discovered that some people with sickle cell disease had fewer symptoms because they never stopped producing gamma-globin. And that gave them the idea that instead of using beta-globin, they could reactivate the gene for gamma-globin by targeting one of the genes that regulates its expression.

It turns out that strategy might actually be easier, because it involves editing a gene to deactivate it rather than putting in new DNA. And because of this, more of the cells seem to go back into the bone instead of dying. Also, it’s not just a treatment for sickle cell, several other blood disorders that are caused by issues with the beta-globin gene could potentially be treated by turning gamma-globin back on.

Like beta-thalassemia, for example, where errors in the beta-globin gene mean the person makes very little or no hemoglobin. So far, animal studies have suggested the technique is really effective, enough for human trials in patients with beta-thalassemia, which started in Europe in 2018. Of course, only time will tell which, if any, of these gene therapies ends up becoming readily available.

But with so many ways to get at the problem nearing or already in human trials, researchers are hoping that something will prove effective in the near future. And they've learned a lot from all the challenges in developing a treatment for sickle cell. The challenges with engineering bone marrow cells and beta-globin genes has led to all kinds of creative solutions, like those lentiviruses and the new research on gamma-globin.

Researchers might have set out to treat sickle cell disease, but in the process they’ve made discoveries that could help with all kinds of treatments. Which hopefully means the future of gene therapy development will go a little more smoothly in the future. If you’re interested in following along with that development, or in learning more about the different types of gene therapy out there and how they work, you should check out the new patient education portal from the American Society of Gene and Cell Therapy.

At SciShow, we are, of course, huge fans of free online education, and if you’re watching this, I’m guessing you are, too. The new portal is a super comprehensive resource for everything gene and cell therapy: there are clear explanations of the more fundamental ideas, along with fantastic summaries of past and ongoing research into different types of treatments. To check it out for yourself, just head over to, or follow the link in the description below! [♩OUTRO].