By David Warmflash, MD | 17 March 2017
We have previously discussed fetal gene therapy. This technique could be considered in particular when a fetus is found to have a condition that is genetic and that will strike at birth, or soon after. Some good examples are diseases of what’s called the beta chain of hemoglobin. Your body tissues require a constant supply of molecular oxygen (O2). Hemoglobin is a very special protein that has evolved to transport O2 in blood, along with some other gases. There’s another chain in hemoglobin, called alpha, but the gene for beta is subject to various mutations. One kind of mutation causes sickle cell disease, where the beta chain is mutated in a way that causes red blood cells to change their shape, which blocks blood vessels in organs, including the brain. Other mutations of that same gene cause beta thalassemia, where the beta chain is either not produced or production is tuned way down. In the womb, however, a fetus that’s destined genetically for either of these diseases is perfectly fine. That’s because the fetal form of hemoglobin doesn’t use beta chains. Instead, it uses a related chain called gamma, which is made by a different gene. However, to get ready for birth, we can imagine a future gene therapy designed to replace, or repair, a fetus’ beta gene soon after birth, or even before birth. This would constitute fetal gene therapy.
The embryo is less mature than the fetus. Therefore, one might assume that modifying genes of an embryo is just another kind of gene therapy, but at an earlier stage. Actually, it would be gene therapy if it were performed to eliminate a disease. But there’s an important distinction. When you read or watch stories about genetic modification of embryos, at present, they are talking about trying to change genetic sequences in all of the embryo’s cells. Modifying only some of an embyro’s cells would be considered a failure since it would lead to a condition called ‘mosaicism’ – having one genetic makeup in some of your cells and another genetic makeup in your other cells. Mosaicism is one of few things that went wrong when Chinese researchers tried to remove beta thalassemia from human embryos using what’s called CRISPR editing in 86 human embryos in 2015.
Genetically modifying all cells of an organism is different from standard gene therapy, where the idea is to change genetic instructions only in selected tissues. In the case of sickle cell disease and beta thalassemia, this means modifying stem cells in bone marrow that produce red blood cells. The rest of the person is unchanged, including his or her reproductive cells. This means that gene therapy does not affect future generations.
With genetically modified embryos, on the other hand, the goal is to edit everything. All cells of an early embryo are some kind of stem cell. Therefore, they can create many different types of cells, including those that ultimately give rise to eggs and sperm. This means that embryonic editing would be a type of germline editing – changing the genetic instructions of the reproductive line. This is what has many people worried, and what fueled criticism following the Chinese experiment. In that experiment, along with mosaicism, there were “off-target effects”, meaning that some genes were inadvertently changed. On top of this, most of the embryos weren’t modified at all, because the genetic payload did not penetrate.
All of this means that we are not ready at all to edit human embryos that actually will be used for pregnancies, but does this mean there should be limits on research? The Chinese researchers were careful to use embryos that were not viable in the first place, because they had an extra set of chromosomes. On top of this, they were no older than 14 days in order to conform to international guidelines, so there really was no legal or ethical issue, even if some of the media coverage made it sound that way.
Reprinted with permission from The Pulse.
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