Changing DNA in a Cell With No DNA: Gene Therapy for Blood Disorders

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]


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