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Below is an adapted excerpt from the new book CRISPR People, reprinted with permission of the author.

I see no inherent or unmanageable ethical barriers to editing the human germline genome. On the other hand, I see very few good applications for it. This is mainly because other technologies can achieve almost all the important benefits of human embryo genome editing, often at lower risk. Two such technologies are particularly remarkable: embryo selection and somatic genome editing.

Editing genes against embryo selection

The most obvious potential benefit would be the editing of embryos or eggs and sperm used to make embryos to avoid giving birth to children whose genetic variations would give them security or a high risk of a specific genetic disease. And here it is time to explain the ways in which genetic diseases or other traits are inherited. If the disease or trait depends on only one gene, we call it the Mendelian condition or trait, named after Gregor Mendel, the Austrian monk who first discovered this type of inheritance. If more than one gene is involved, we skillfully call them non-Mendelian conditions or traits. Much of the discussion below is about Mendelian conditions for the simple reason that there is more to be said for them.

Mendel̵

7;s conditions can be largely divided into five main categories, depending on where the DNA is located and how many copies of the disease-causing variant are needed to lead to the disease: autosomal dominant, autosomal recessive, X-linked associated with Y or mitochondrial. Autosomal dominant diseases require only one copy of the disease-causing genetic variation; autosomal recessive diseases require two copies, one from each parent. X-linked diseases usually require two copies in women (one from each parent), but only one in men (who have only one X chromosome, always inherited from the mother). Y-linked diseases, which are uncommon, occur only in men and require only one copy – because only men have the Y chromosome and usually have only one copy of it. Mitochondrial diseases are inherited only from the mother and any mother with the disease will inevitably pass it on to all her children.

Why take the new, riskier – and for many people embarrassing – path of genetic editing, and not just choose embryos?

Thus, if an embryo has 47 CAG repeats in the corresponding region of its hunting gene, it is doomed (if born) to have autosomal dominant Huntington’s disease. Germ line editing can be used to reduce these 47 repetitions to a safe number below 37 and thus prevent disease. Or, if the embryo has two copies of the genetic variation for Tay-Sachs autosomal recessive disease, it can be edited so that the embryo has one or no copies and is safe. The same is true for X-linked, Y-linked or mitochondrial diseases.

If this is safe and effective, it may make sense. But another technology that has been in clinical practice for about 30 years is known to be (relatively) safe and effective and can do the same – PGD [preimplantation genetic diagnosis]. PGD ​​involves taking one or more cells from an ex vivo embryo, testing the DNA in those cells, and using the results to determine whether to transfer that particular embryo to a woman’s uterus for possible implantation, pregnancy, and childbirth. The first baby with PGD was born in 1990. In 2016, the last year for which data are available, the US Centers for Disease Control and Prevention (CDC) reported that about 22% of the approximately 260,000 cycles of IVF performed this year in the United States included PGD (or a version called preimplantation genetic screening, or PGS). This was compared to about 5 percent a year earlier. Anecdotally, talking to people working in IVF clinics sounds as if the use of PGD or PGS in 2019 could be over 50%, at least in some parts of the United States.

If a couple wants to avoid giving birth to a child with an unpleasant genetic disease or Mendel’s condition, they could, after a decade or more, use CRISPR or other gene editing tools to change embryo variants to a safer form, or today you could use PGD to find out which embryos are carrying or not carrying dangerous variants. For an autosomal recessive condition, an average of 25% of embryos will be affected; for autosomal dominant – 50%. Even under dominant conditions, if one examines 10 embryos, the chance of all 10 having the “bad” version is one in 1024. If you have 20 embryos to test, it becomes one in 1,048,576.

So why take the new, riskier – and, for many people, embarrassing – path of genetic editing, and not just choose embryos?

Credit: JAAFAR ASHTIYEH via Getty Images

Editing genes in somatic cells against germ lines

Somatic cell therapy does not alter the germ line and involves technology much closer to being shown to be safe and effective than human germline genome editing. It is arguable that the fact that the change is made in only one or more of the many tissues of the body would improve its safety due to a change that exists in every cell, including cells where a particular non-target change has harmful effects.

On the other hand, editing the genome of an egg, sperm, or zygote only needs to change one cell. This may be more effective than changing, say, 100 million hematopoietic stem cells or several billion lung cells. In addition, somatic cell editing does not have to work in all conditions. Some may require too many different cells or tissues. For others, the disability may begin before birth or even before the stage of fetal development, when intrauterine somatic editing becomes plausible. In diseases with very early side effects, somatic cell therapy may be inferior to embryo editing or embryo selection.

Even when somatic editing is possible, editing the human embryo genome retains one advantage: the process should not be repeated in the next generation. If somatic editing is used, this person will still have eggs or sperm that can transmit the disease. If she or he wants to avoid a sick child, PGD or somatic cell therapy may be needed. If germline editing is used, that child’s children will be at no risk of inheriting the disease from their edited parents. But is this a bug or a feature? It adds a choice – not a choice for the embryo that is or has not been edited, but for the parents of that embryo. Editing somatic cells continues the possibility of disease in the next generation – but allows the parents of that generation to make a decision. One can – or not – see this as a benefit.

Gene editing in multigenic diseases

In non-Mendelian (sometimes called multigenic) diseases, no variant plays a powerful role in causing the disease. Variations in two, twenty or two hundred genes can affect the condition. Collectively, these influences can be 100 percent, although the cases we know now provide much lower certainty. We still don’t know of very good examples, although at least one article claims to have found strong evidence that variations in different genes working together increase the risk of some cases of autism. And more generally, we know of many combinations of shared genomic regions that (slightly) increase or decrease the risk of various diseases or traits in particular, studied populations. (They have led to a “polygenic risk assessment” hotspot, the ultimate importance of which remains to be seen.)

The biggest problem with editing the human embryo genome for non-Mendelian conditions is that we don’t know almost enough about the conditions. We believe that many conditions are not Mendelian, but how many genes are involved? Which genomic variations add or remove risk? How do the effects of variations from different genes combine to create risks? In a simple world, they would be additive: if the presence of a specific variation of a gene increases a person’s risk of disease by 10 percentage points, and the presence of a specific variation of a different gene increases that person’s risk by 5 percentage points, then both would increase the risk by 15 percent. But there is no inherent reason for nature to work this way; the combined effects may be greater or less than their sum. It is even possible to have two variations that, individually, increase a person’s risk, may in some way reduce the overall risk. We know almost nothing about the structure of these non-Mendelian or multigenic risks.

It is clear, however, that in general PGD would be much less useful for non-Mendelian diseases than for Mendelian. The chances of finding an embryo with the “right” set of genetic variations in five different places in the genome will be much lower than finding an embryo with just one “correct” variation. If the chances of any variation are 50/50, the total chances of every five variations in an embryo are one in 32. If gene editing can safely and effectively edit five sites in the embryo’s genome (or in the genomes of two gametes) ) may result in the preferred result. On the other hand, if we can use genome editing to do this in an embryo or gamete, we may be able to do the same in a fetus, baby, child, or adult through somatic cell gene therapy – unless the condition begins to cause damage at the beginning of development or wide enough in the body that it must be delivered to all cells of the body.

Is gene editing practical?

There is currently no non-Mendel state that we are sure we know the exact set of genes involved. Nor do we know the negative and positive effects of different combinations of genetic variants. Until these uncertainties are adequately resolved, editing the human embryo genome, although in theory better than PGD, will not be safe or effective enough to use. Once resolved, in many situations this will not be better than editing genetic somatic cells, except for the possible absence of the need to hit targets in multiple tissues or cell types and the lack of need to repeat editing for the next generation. .

Adapted from CRISPR PEOPLE: The science and ethics of human editing by Henry Greeley. Copyright 2021. Reprinted with permission from MIT PRESS.


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