Heritable Genome Editing (HGE)

What is HGE?

In an early stage embryo, sperm, or egg, a specific sequence of DNA is being replaced. Genetic material is added or altered. This is also called Human Germline Genome Editing. The edited DNA becomes part of the genome of that child and will be passed on subsequent generations, therefore becoming part of the human gene pool. One the techniques is called CRISPR-Cas9. (clustered regularly interspaced short palindromic repeats - CRISPR-associated protein 9, see below).

Heritable Human Genome Editing (HHGE) interventions in clinical applications are not currently available, but they could be in the future.

Because Scientists propose this to be used clinically, such as to "edit-out" inherited diseases or even for the "enhancement" of human capabilities. They assert that Genome Editing will have extensive therapeutic potential.

There are considerable worries about the safety of those techniques. There is the term of 'off-target' genetic modification, an unintended modification, which can alter the function of DNA. This would mean the clinical application is flawed with unpredictable results. The flaws would be passed on to the next generation.

 The other application of HHGE on embryos is for basic research and not for reproductive purposes. Genome editing research uses human embryos, with regard to better understand the early embryo development and the transformation in genetic diseases. In some countries this is permitted.

Thus there are 3 ways in which Heritable Human Genome Editing (HHGE) is proposed to be used:

1. HHGE on embryos for basic research (non for reproductive purposes)

2. HHGE for clinical application (for reproductive purposes, heritable)

3. Enhancement of individuals (prospect of altering an embryo, by non-therapeutic intervention intended to improve or extend a human trait)

Would it be justifiable to pursue the basic research application of HHGE? There is a slippery slope from using HHGE only in basic research, to using it for clinical application, to finally the enhancement.

In 2018 Dr. He Jiankui published a paper, where he announced that he had created the world's first gene-edited babies, twins, who's genome had been edited for HIV resistance. He shocked the world's scientists, and they condemned Dr. He’s actions. The consensus was that the gene-editing technology is too premature to be used for reproductive purposes. Dr. He Jiankui was sentenced (3 years in prison) for violating China's bans on the clinical application of gene-editing for reproductive purposes.

Clinical Application of HHGE?

The clinical applications of HHGE would be:

• Preventing the transmission of genetic variations that come along with severe genetic diseases (single gene disorders)

• Reducing the risk of common diseases (polygenic diseases), with the promise of improving human health

• Enhancing human capabilities far beyond what is currently possible for human beings, thereby overcoming human limitations. (Human Enhancement)

"Severe genetic disease": What is severe? What is seen as "severe", is an extremely loaded expression of an emotive and cultural construction.

Safety concerns regarding HHGE:

There are unintended changes to the genome (called 'off-target', 'on-target' and 'mosaic'), which could possibly lead to cancer and other disabling pathologies. This would make the clinical application of HHGE rather ineffective. The child and subsequent generations could have unpredictable diseases at unpredictable times of their lives, which would make long-term follow up almost impossible.

The clinical application of HHGE is controversial:

Prevention of suffering is usually quoted in this context, but Heritable Human Genome Editing is carried out before the symptoms appear. Therefore the argument in favour of those interventions seems to be on wobbly chairs.

Proponents suggest that

• the safety risk associated to off-target mutation shouldn't hamper the pursuing of HHGE. Safety risks to participants, they imply, are found in nearly all medical research.

• serious birth defects of genetic origin are found in 6% of all babies being born. Therefor there are moral reasons to prevent the occurrence of these genetic diseases in future generation. The clinical application of HHGE will be there to prevent genetic disease.

Proponents argue that the pursuing of HHGE is morally permissible and morally desirable.

What is CRISPR?

The technology of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) refers to a whole range of molecular snippers-and-pasters. Scientists have been using these molecular scissors to cut human DNA. The scientists favour this technique, because they say, it is faster, cheaper and more accurate than other genome editing techniques. They profess it to be an accurate way of deliberately altering any genome.

The technique of CRISPR-Cas9 follows a specifique immune defense of bacteria. They capture small pieces of the DNA of the infecting virus, insert them into their own DNA as CRISPR, which allow the bacteria to remember the virus. The newly attacking virus get counteracted by the CRISPR-Cas9 enzyme which cuts the DNA of the virus at that specific region, which disables the virus.

This immune defense system by bacteria was adapted by Scientists to edit DNA. When the CRISPR gets introduced into a cell, it recognizes the intended DNA sequence, and the Cas9 enzyme cuts the DNA at the targeted location.

Genome editing is also called genome surgery, and the CRISPR mechanism is explained through the image 'gene scissors'.

Though genome editing is known for its glitches. There is talk of 'off-target', 'on-target' and what is referred to as a 'mosaic'.

'Off-target' refers to when gene segments are modified where they were not targeted.

'On-target' refers to when the cell’s own repair mechanism contravenes the attainment of the desired outcome of the gene modification.

'Mosaic' refers to when the genetic modification takes effect in a certain segment of the targeted cells, not in the same way as it should be in all treated cells. (Mosaicism means incomplete editing of only some of the cells in a multicell embryo)

All glitches could lead to harmful consequences. The possible short- and long-term harm from genome editing, including the possible consequences unintended off-target effects and unwanted on-target effects and of genetic mosaicism, must be completely understood before options for such medical applications are considered.

Questions:

• Is it justifiable to proceed with the clinical application of HHGE?

• Do you think that the clinical application of HHGE is irresponsible, due to the considerable safety problems (medical and social) of the new technique?

• If the procedure for somatic (non hereditary) genome editing would be considered as medically safe, would germline (hereditary) genome editing fall under the same assumption?