MYBPC3: Editing the Human Germline

So, last week it was published. For some the breakthrough, for others the breaking of taboos. Researchers around the controversial stem cell guru Shoukhrat Mitalipov have “CRISPRed” out a serious hereditary disease from human embryos. Hopefully most of my readers know by now that CRISPR are those amazing “gene scissors” that can be designed in such a way that they can create a DNA double-strand break at (almost) any point in the genome. If, at the same time as this, CRISPR is programmed against a certain defective gene, a “healthy” variant of this gene is introduced into a cell, there is a high chance that this cell will replace the disease-causing gene with the correct variant. And if this cell is now a fertilized egg cell, then all the offspring of this cell and with it the entire organism will carry the repaired gene version.

Well, Mitalipov and his team repaired a mutation in the MYBPC3 gene in human egg cells in exactly this way. This MYBPC3 mutation is responsible for almost half of all cases of hypertrophic cardiomyopathy. This was worth an article for the journal Nature this week along with considerable accompanying coverage. The problem I have with this is that such a repair of hereditary diseases in human embryos has already been described three times by Chinese scientists in the past two years, but has never been published in such a high-profile journal. On the contrary, the common sense in the Western research community was that you shouldn’t “CRISPR around” on human embryos for the time being. So now Mitalipov’s group, based in Portland, USA, is doing just that, and it’s being made into a big article.

So again, one after the other: as I already described in more detail in the background article on genetic engineering, CRISPR came along in 2012 and revolutionized the field. This new methodology was groundbreaking and almost every molecular biology laboratory in the world has started working with it. Because CRISPR as a tool is so universal that it is incredibly practical for almost any genetic application, for immunologists, cancer researchers or even ecologists alike. And it was clear to everyone that things like designer babies – previously a dystopia that was far in the future – had suddenly come within reach. An appeal was made (by the way in Nature) calling for the technique not to be used on human embryos because it had not yet been studied in sufficient detail.

But even before a summit was held in Washington in December 2015 to develop more precise guidelines, the work of a Chinese group from Guanzhou was published. The Chinese researchers used CRISPR to repair the beta-globin gene (HBB) in human embryos, which causes beta-thalassemia in a certain form. This work was published in the relatively insignificant journal Protein & Cell (with an impact factor of about 5) after both Nature and Science rejected it.

A second work by Chinese researchers on editing the human genome using CRISPR was similar. The article describing how the CCR5delta32 mutation was introduced into human embryos, making them immune to HIV, was published in the even less significant Journal of Assisted Reproduction and Genetics (impact factor of about 2). The researchers of both teams worked on human egg cells that were rendered incapable of development by a trick in order to quasi “ethically defuse” their work. Thus, regardless of the success of the CRISPR-induced change, these egg cells could not develop into viable embryos.

And at the beginning of this year there was a third publication in which genetic defects, this time in viable human egg cells, were repaired using CRISPR. Again you had to search for the article in a pretty insignificant journal (Molecular Genetics and Genomics, impact factor of about 3). Notably, the success rates, which were still moderately convincing in the first two papers, were considerably better this time.

So now Mitalipov, a researcher who resides in the USA, has submitted his work on CRISPRed embryos and Nature (with an impact factor of over 40) makes it a big story. I had a closer look at it: Mitalipov of course also repairs a mutation which is the basis of a hereditary disease (and does not destroy, for example, myostatin to produce babies with giant muscles). In the case of his paper, it’s the MYBPC3ΔGAGT mutation, which causes the hypertrophic cardiomyopathy mentioned above, i.e. a thickening of part of the heart. If this disease is recognized early, it is quite treatable. Undetected, however, it is often the cause of sudden cardiac arrest.

In contrast to the Chinese, who first injected their CRISPR constructs into the already fertilized egg cell, Mitalipov’s group has introduced the CRISPR cocktail into the egg cell at the same time as the sperm. For the first time, it was achieved that the CRISPR system actually did something in 100% of all cells examined. However, it only really incorporated the correct sequence and repaired the gene in 72% of all cases. In the remaining 28% of the cases, the cell responded to the DNA double-strand break caused by CRISPR by patching the open ends back together, regardless of loss of some genetic material. Unfortunately, this process creates new errors; the old mutation was therefore replaced by a new mutation. In the abstract of the article, however, the authors write rather reluctantly that the general applicability of this whole CRISPR matter has now been shown and that the only thing left to prove is the reproducibility or the applicability to other mutations.

There would, however, definitely be other objections to applying the CRISPR system to the human germ line. The germline is essentially the continuous developmental line of cells that are created in the early embryo as egg or sperm cells and thus later contribute to the next generation. A genetic change that is introduced into a fertilized egg cell will be present in all body cells (including egg or sperm cells). It is thus passed on to all future generations. Some critics see one of the most important principles of modern medicine being violated here: informed consent. This demands that all people who are undergoing a medical procedure must first be informed about the corresponding procedure and then, given this knowledge, can freely decide whether they want to undergo this procedure.

In the case of children (and incidentally also, for example, unconscious, seriously injured accident victims), however, we are already adopting a different approach: we assume that they want to undergo an operation that ensures their freedom from pain or even their continued life and decide on their behalf. So why shouldn’t we do the same for people who haven’t even been conceived today?

So there are arguments both for and against the manipulation of the human germ line. Here, we only touched on a fractions of the arguments which can and are being made in this discussion. This makes clear how urgently we need a broad discussion on this subject at the moment, so that the public does not again – as in the genetic engineering PR disaster – have the feeling that they are being overwhelmed by the creepy excesses of a blind greed for progress.

In conclusion, I would like to state briefly: At the moment I do not have a final opinion myself about this type of application of CRISPR, because there are still so many points, especially risks, to be clarified. But I think ethical precautions and guidelines that a world-class international journal imposes on itself should be the same for researchers in Guangzhou as they are for researchers in Portland. I therefore find it somewhat schizophrenic that Nature published an appeal about two years ago that warns of the modification of the human germ line and rejects corresponding articles from China as long as a whole series of risks has not been crucially weighed. Mitalipov’s article was published last week; and that although in the past two years nothing noteworthy has certainly not happened in terms of risk assessment.

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