Germline gene therapy: should we open the box on a brave new world of designer babies?
Written by: Munaye Lichtenstein
Art by: Cheng-Yu Huang
On St Valentine’s Day 2017, a new report from the National Academies of Sciences, Engineering and Medicine USA was published on clinical trials for germline gene therapy. The report concluded that ‘adding, removing, or replacing DNA base pairs in gametes or early embryos – could be permitted in the future, but only for serious conditions under stringent oversight’ and outlined the criteria to be met before allowing germline editing clinical trials to proceed.
But what exactly is germline gene therapy? It is the transference of genes into germline cells – the sex cells, oocyte and sperm – a therapeutic that serves to potentially eradicate rare inherited genetic disorders, such as Huntington Disease, by deleting and replacing the faulty genes that cause them.
Germline gene therapy differs from somatic gene therapy, where a gene is introduced to the somatic (body) cells aiding only the recipient. Somatic gene therapy has already entered clinical trials for non-heritable applications and the report also stated that this should only be allowed for treating or preventing diseases or disabilities.
But germline gene therapy offers a permanent change, one which would be inherited by future generations. It has, however, been considered scientifically challenging and perhaps unethical for a long time. In the UK the editing of germ cells and embryos in clinical cases is currently illegal.
The difficulty faced by scientists in gene therapy has thus far been how to successfully deliver the foreign DNA into cells. With somatic gene therapy a host of delivery methods have been explored: the two major methods are use of viral vectors and nonviral methods, the former being the more popular of the two. The use of recombinant viruses to incorporate genes into the genome takes advantage of the virus’ ability to invade its host cell, making several copies of itself by manipulating the host’s own replication machinery. This, however, does not come without problems as viral systems may introduce toxicity.
The scientific barriers faced by somatic gene therapy are arguably fewer than those faced by germline gene therapy. Although germline gene therapy has been successfully applied in some animals, this is not without great difficulty. The gene may fail to be introduced, or if successfully introduced, be inactivated. While these problems would have no real risk, there is very real concern if there are partial or multiple copies of the transgene (foreign DNA). The prospect of mosaicism in embryos (irregularities in chromosome number and arrangement) is a worry too, as it could either result in an individual who is phenotypically normal, or it could potentially have catastrophic consequences. Therefore, to perform the therapy in humans knowing the risk would be irresponsible. Targeting of the genes introduced is another issue, as an insertion of a gene into unintended loci may interfere with the actions of other genes.
Germline gene therapy has already been performed in animals: you first carry out gene replacement in embryonic stem cells and then select and grow cells, before injecting these into the blastula to get a chimaeric T1 generation. You then cross that to segregate, so creating a transgenic animal. Even if delivery of the transgene into the human genome were to be successful, there are still great risks; the human genome is not fully understood and so to alter it, especially considering that the results of germline gene editing could not fully be known until after birth, would be reckless. The luxury of testing on animals is not afforded to humans – you have to get it right the first time, making the use of the therapy in humans currently ethically impermissible.
But, the relatively recent discovery of the CRISPR-Cas system has allowed the prospect of germline gene therapy to become more feasible. CRISPR-Cas (clustered regularly interspaced short palindromic repeats, and CRISPR-associated proteins – Cas) is part of bacteria’s adaptive immune system and acts by recognising and cutting foreign DNA invading the bacterial cells such as bacterial viruses (also known as bacteriophage, or phage for short).
There are multiple CRISPR mechanisms, type II being the most well studied, which acquires new immunity by fragmenting the foreign DNA from invading plasmids or phage and inserting them into the CRISPR locus on the bacteria’s own genome, alongside a series of short repeats. These loci are then transcribed into RNA, processed to make small RNAs known as crRNAs, which act to guide the effector endonucleases (enzymes that cut DNA at specific sites) to target the invading DNA based on complementary DNA sequences. The discovery of CRISPR-Cas is somewhat revolutionary in biotechnology, with applications in many areas of science.
Germline gene therapy requires homologous recombination to replace a mutant gene. But this process is inefficient and DNA integrates randomly by so-called ‘illegitimate recombination’. The relevance of CRISPR is that it makes gene targeting by homologous recombination much more efficient, as you can make a targeted cut at the gene you seek to replace. Using CRISPR therefore increases the likelihood of the gene getting repaired; the scientists, by also making the wild type gene available, can replace the faulty gene present in the genome.
Possible ways do this in humans would be to inject the foreign DNA into a fertilised egg, letting it grow into a blastula in vitro and screen sample cells for the correct targeting event. Then if a fertilised egg is found – which may not happen as this is likely to be an extremely inefficient process – it is implanted. Alternatively you could take embryonic stem cells and perform the gene targeting in those, then screen to identify the correct event. The nucleus could then be removed and transferred into an enucleated egg cell.
The problem still remains, regardless of using CRISPR, that there could be unpredictable consequences of germline gene editing, not to mention accidental errors. If germline gene editing were to be used in human embryos there could be unforeseen repercussions on fetal development and unknown long-term side effects.
A Question of Morality?
Beyond the scientific challenges that face germline gene therapy, there is also an ethical debate about its use. Universal healthcare is unfortunately not universal, and the cost of the therapy would inevitably make it only available for the wealthy. A fear exists that if used it could create a warped utopia reserved exclusively for the rich. There are questions as to whether the therapy would be used to enhance traits such as height and intelligence – creating ‘designer babies’, treating future generations as a commodity.
Would this create more of a divide? Not only would those from poorer backgrounds have to face a socioeconomic but now also a genetic disadvantage. Some of the world’s greatest achievements have been made by individuals conquering their adversity; surely there is a danger in removing such individuals from the population. Future generations also cannot consent to their genetic information being edited, and individuals with a genetic condition may argue that their disease has given them a unique perspective on life, an experience that, although difficult, is defining: to take that away would be to discredit their existence. There too is a strong argument that by removing these individuals from the population our society would consequently become less accepting of those with disability.
Where is the line drawn? Who deems which traits are a disability? Who is to say that someone with a condition such as Down syndrome cannot live a life as rich and meaningful as someone without?
Moral and science dilemmas aside, there is a case as to whether this therapy is even necessary. There are various alternatives for couples seeking to have children who do not want them to inherit a genetic disorder that runs in their familial lines. IVF – in vitro fertilisation – followed by PGD – preimplantation genetic diagnosis – is an example of an alternative. PGD looks for at-risk embryos by removing a cell from an embryo in vitro to test for a specific genetic disorder. For recessive mutations, even if one parent is homozygous for a genetic disease and the other is heterozygous for the same disease, it will still be possible to to produce a healthy baby.
Recently three-parent babies have become legal in the UK, tackling rare inherited mitochondrial diseases. Mitochondria, the ‘powerhouse of the cell’, are inherited from the mother alone. In this therapy, a couple will use the mitochondria of another female – let us call it ‘organelle donation’. The first child was born using this method in September 2016, in México. With all these alternatives, the question is raised as to whether germline gene editing is necessary; perhaps investment is better placed in improving somatic gene therapy, which is appropriate for a wide range of disorders such as cancers, infectious diseases, and inheritable diseases such as sickle cell anaemia. Improving delivery mechanisms and the therapies’ effectiveness is surely more of a priority.
There is always great fear surrounding some areas of science but gene editing, and germline gene editing in particular, could potentially offer a profoundly powerful approach to treating and preventing heritable disease. The debate on whether germline gene editing should be used continues as the understanding of the field of genetics grows with the aid of technological advancements. But, for the moment, heritable gene editing is not ready for use in humans: we are not yet ready to take on the mantle of ‘intelligent design’…