Gene flow in hypothetical genetically engineered humans

[rfranceschetti]

Hi all,

It has come to my attention this article on PF (https://www.physicsforums.com/insights/can-gene-editing-eliminate-alzheimers-disease/) about a genetic approach to prevent Alzheimer's disease, based on applying gene-editing techniques on human embryos. In short (so not to be repetitive), the idea is to introduce a variant of the APP (amyloid precursor protein) gene that prevents the formation of amyloid-β-peptide aggregate in brain cells, a product of the amyloid precuror protein (you can get an in-depth explanation of how it occurs in the mentioned article).

The author talks about potential prejudices (or the absence thereof) against GE humans or non-GE humans, and also the problem where the treatment remains stricted to the wealthy. However, financial resources shouldn't be a problem, should it? Considering gene flow phenomenon, wouldn't the gene pool of the local population be altered by the introduction of the desired APP gene in a few individuals?

By the way, I am aware that we are quite far, both ethically and scientifically, from editing human genes. This is purely a hypothetical question.

Thanks,
Rafael

P.S.: I created a thread to discuss it because I couldn't make a reply in the original article.

 

[BillTre]

Considering gene flow phenomenon, wouldn't the gene pool of the local population be altered by the introduction of the desired APP gene in a few individuals?

Yes it would, because new genes are being put into the breeding population.
If the new gene is being inserted into a place in the genome where the normal version of the gene does not normally reside, in would be also adding that new location for the gene into the population also.

 

[rfranceschetti]

Yes it would, because new genes are being put into the breeding population.
If the new gene is being inserted into a place in the genome where the normal version of the gene does not normally reside, in would be also adding that new location for the gene into the population also.

So you don't really have to edit every embryo you want to be protected, you "just" need to edit a strategic number of individuals in specific regions of the country. Is it possible to perform the editing in somatic cells only, therefore blocking the possibility of gene transfer?

Regarding changing the gene location: doesn't the mutated gene have to be inserted specifically in the region of the original gene to function properly?

Thanks for your answer.

 

[BillTre]

So you don't really have to edit every embryo you want to be protected, you "just" need to edit a strategic number of individuals in specific regions of the country. Is it possible to perform the editing in somatic cells only, therefore blocking the possibility of gene transfer?

No. That's different from just getting the gene pool into the local population. Just putting a different gene into a local breeding populations gene pool will not provide any protection against anything in any individuals not themselves carrying the gene.

• If you want every embryo protected, you would need to either modify them all, or modify one or a few with a gene that would be adaptive in the population and let them breed for a few generations to get the gene into a larger proportion of the overall population. This still may not get the gene into all individuals and leave some unprotected.
  
• If the gene had to be homozygous to achieve its positive effect, more breeding would be needed to get rid of the other versions of the gene in all individuals. This might be difficult depending on genetic details.
  
• If your plan is to involved breeding steps you will have to be modifying germ cells or the genetic modifications would not be passed on to any offspring.

In theory, germ cells can be modified by having gene drives linked to the new inserted gene. This can cause the new sequence to spread more rapidly through a breeding population by changing the way it is inherited. There are even more ethical considerations about gene drives because of the potential to modify whole populations.

 

[Ygggdrasil]

The author talks about potential prejudices (or the absence thereof) against GE humans or non-GE humans, and also the problem where the treatment remains stricted to the wealthy. However, financial resources shouldn't be a problem, should it? Considering gene flow phenomenon, wouldn't the gene pool of the local population be altered by the introduction of the desired APP gene in a few individuals?

Yes, the gene could spread throughout the population through interbreeding. However, this would also create potential prejudices as the GE humans may be considered more suitable mates than non-GE humans (since only by mating with a GE human would your children have the chance of carrying the protective allele). Of course, one could already argue that this is the case as different individuals carry different genetic traits seen to be beneficial or deleterious. Widespread access to germline-gene editing and/or pre-implantation genetic diagnosis would eliminate these potential concerns with mate choice.

By the way, I am aware that we are quite far, both ethically and scientifically, from editing human genes. This is purely a hypothetical question.

We are not quite as far away as you think. This week, scientists in China reported the first gene editing experiments on viable human embryos: https://www.newscientist.com/articl...chnologies-wont-lead-designer-babies/']crispr-gene-editing-of-normal-embryos-released[/URL]

Is it possible to perform the editing in somatic cells only, therefore blocking the possibility of gene transfer?

Yes, though there are challenges with this approach. Sometimes gene editing would have to target all cells in a certain cell population (this may be the case for the protective Alzheimer's allele). Somatic gene editing would have to be 100% efficient in all cells in a tissue, a very difficult benchmark, whereas germline gene editing would just have to affect one or a few cells in a germline precursor or embryo. Furthermore, some tissues are more easily accessible for gene editing than others (e.g. it would be easier to perform routine editing of embryos in a dish than to perform brain surgery to edit the DNA of living people's brains).

Regarding changing the gene location: doesn't the mutated gene have to be inserted specifically in the region of the original gene to function properly?

In many cases, yes. However, in some cases (especially those in which you are correcting the function of a faulty gene), the gene can be inserted randomly into the genome. This is the approach used for recent gene therapy trials correcting sickle cell disease: https://www.physicsforums.com/threa...in-one-patient-for-at-least-15-months.906352/

Of course, random insertion of DNA into the genome carries the risk of disrupting important genes and causing diseases such as cancer. In almost all cases, editing the endogenous gene locus would be preferable.

 

[rfranceschetti]

I might be making some confusion, but that's what I meant by suggesting the edition of only a few individuals: eventually, after some generations, the desirable gene would have spread to a larger population. I suppose the problem of the favourite mate would only occur in the beginning, because of the initial low frequency of the editted gene, but after some time, the gene would be reasonably well distributed in the region (even if it takes decades, let's just consider the possibility for a momment).

About editing somatic cells only: couldn't you edit only a few somatic cells of the cell population and let mitosis substitute the unedited cells with the GE ones? (In the process of maintenance, changing of damaged/dead cells etc).

 

[BillTre]

About editing somatic cells only: couldn't you edit only a few somatic cells of the cell population and let mitosis substitute the unedited cells with the GE ones? (In the process of maintenance, changing of damaged/dead cells etc).

Yes, they could possibly divide and replace other somatic cells, possibly all of them in cell population undergoing a lot of turn over.

In most animals (including mammals), germ cells can not be derived from somatic cells after early development.
Therefore, mitosis would not be able to get them into cells that would be involved in generating the next generation.
It could work in plants though. Germ cells are not in a distinct developmental lineage in plants.

 

[Ygggdrasil]

About editing somatic cells only: couldn't you edit only a few somatic cells of the cell population and let mitosis substitute the unedited cells with the GE ones? (In the process of maintenance, changing of damaged/dead cells etc).

The GE cells could just as easily be replaced by the much more numerous unedited cells. Furthermore, there are some tissues, such as the brain, where cell turnover does not occur. The extent to which somatic cell editing would work depends a lot on the type of disease being addressed. If you are interested in reading further on the issue, here's a nice review article discussing some of the challenges in developing gene editing therapies: http://www.nature.com/nm/journal/v21/n2/abs/nm.3793.html

 

[rfranceschetti]

The GE cells could just as easily be replaced by the much more numerous unedited cells. Furthermore, there are some tissues, such as the brain, where cell turnover does not occur. The extent to which somatic cell editing would work depends a lot on the type of disease being addressed. If you are interested in reading further on the issue, here's a nice review article discussing some of the challenges in developing gene editing therapies: http://www.nature.com/nm/journal/v21/n2/full/nm.3793.html

I see. Based on your work experience, do you think it's possible to make an estimation of how long it'll take to fully develop this technology and make it large-scale applicable?

 

[Ygggdrasil]

Ex vivo gene editing of somatic cells could potentially enter clinical trials in the next few years for treating conditions such as hemophilia and sickle cell disease as well as for engineering T-cells for cancer immunotherapy. We are probably more than a decade away from therapies involving in vivo somatic gene editing. I'm not sure when we might begin to see germline gene editing. Probably within the next 5-10 years, researchers will begin to perfect embryo editing while performing experiments to study embryo development. A game changing method here would be the ability to harvest normal cells from an adult, reprogram them into stem cells, then guide those stem cells to develop into germ cells in the laboratory. While people are working on developing this technology, its unclear when these capabilities will be demonstrated. Still, almost all of the benefits from germline gene editing could be achieved more safely from PGD.

As I mentioned in my https://www.physicsforums.com/insights/dont-fear-https://www.physicsforums.com/insights/dont-fear-crispr-new-gene-editing-technologies-wont-lead-designer-babies/-new-gene-editing-technologies-wont-lead-designer-babies/, we are very far (decades) away from knowing how to edit complex traits like intelligence. Current ethics guidelines suggest limiting germline gene editing to introduce only alleles already widespread throughout the population, so more research will be required to fully determine the safety of rare protective alleles (such as the protective Icelandic allele) before trials could begin. Germline gene editing could be like the idea of flying cars. We probably have the technology to do it, but no one quite trusts society to be able to deal with it.