Australian Lefty on Politics, Governance, Science and Info Management

Great news – pity it’s a new mortal sin

Posted by Dave Bath on 2008-04-03

I’m jumping for joy about a recent Gene Therapy paper, although as it’s definitely in the Roman Catholic mortal sin list, I expect Australia’s own Grand Inquisitor Cardinal George Pell will be jumping up and down in extreme anger.

It promises great reductions in human misery and health costs, but presents a problem for politicians more committed to their electability rather than than the welfare of the population, as well as for lawyers acting on behalf of people afflicted with single-point mutations who want the best for their children.

"Correction of a genetic defect in multipotent germline stem cells using a human artificial chromosome" offers the hope for people with nasty single-base-pair genetic disorders (like Sickle-Cell, Cystic Fibrosis, and a host of nastier syndromes) with the possibility to avoid abortion after a nasty result from foetal testing, yet avoid the need to tinker with genes inside a conceptus by fixing testicular cells before they produce sperm.

Loud cheers for the Japanese researchers, who produced the paper (published online 2008-02-28) with the formal identification "Gene Therapy (2008) 15, 617–624; doi:10.1038/"

Over the fold, I’ll go through parts of the abstract and add explanatory notes, then I’ll talk about the implications and legal/ethical/economic implications.

The only downside is that (as far as I know), the work has been on testes rather than ovaries, so problems when the mutation is in the prospective mother are not addressed (and this affects the possibility of dealing with X-linked recessive disorders.

Human artificial chromosomes (HACs) have several advantages as gene therapy vectors, including stable episomal maintenance that avoids insertional mutations and the ability to carry large gene inserts including regulatory elements.

The insertion of correct genes and the means to control translation/transcription into the "correct" place avoids breaking other genes, as targetting is much more reliable than the random approach with viral vectors, or the ones I used (on E.coli) by putting wholes in cell membranes, dropping the desired raw DNA into the test tube, and shaking hard.  (Indeed, "scattergun" is a good description of a similar approach from the early days of coating minitature gold "bullets" with bits of DNA and firing them into cells!)

Multipotent germline stem (mGS) cells have a great potential for gene therapy because they can be generated from an individual’s testes, and when reintroduced can contribute to the specialized function of any tissue.

Actually, the real advantage is not for reintroduction to an existing adult, (in the hope of fixing other tissues, and useless if the gene product is not merely inactive, but directly damaging, as there will always be cells that don’t get fixed) but fixing the germline itself, and preventing transmission to the next generation.

As a proof of concept, we herein report the functional restoration of a genetic deficiency in mouse p53-/- mGS cells, using a HAC with a genomic human p53 gene introduced via microcell-mediated chromosome transfer. The p53 phenotypes of gene regulation and radiation sensitivity were complemented by introducing the p53-HAC and the cells differentiated into several different tissue types in vivo and in vitro. Therefore, the combination of using mGS cells with HACs provides a new tool for gene and cell therapies.

Again, big deal.  Improving function of one individual is one thing.  Improving the wellbeing of all descendents by a single action, without any of them needing costly treatment, is the elegant way to a huge payoff.

What potential parent wouldn’t rather avoid lots of testing of each conceptus, and destruction (either in vitro, or via a termination) if a serious defect is detected, wouldn’t want to rid their descendants forever of a nasty gene?

But the new list of mortal sins from the Vatican precludes tampering with the human genome, so those Roman Catholics without an appropriately nuanced interpretation of this issue will be up in arms.

Fiddling with the human genome as far as multifactorial conditions, or for "augmentation" is one thing, and I would abhor any such action.  Repairing a gene that is an unequivocal cause with completely characterized aetiology (rather than a mere correlation) is not tampering in my view, is not a nasty ham-fisted form of eugenics, so it should be allowed.

Such nuances, will need to be explained to legislators, and the public.  This topic needs wide debate soon, because this is any example of scientific progress and possibilities moving faster than our legal and political systems seem capable of dealing with.

Personally, I think that the class of such interventions is highly desirable, but that every gene capable of being repared is submitted for approval to an expert committee, dominated by clinicians who have experience with the consequences of the disorder, and pathology experts who can assess the reliability of the cause and effect.

I’d also argue that single point mutations, where a single base-pair is the culprit, should be the only candidates for such treatment, at least in the medium term.

Mind you, there are complications.  Sickle-cell anæmia is a point mutation that causes the sixth amino acid in the Beta-Globin chain in hæmoglobin to be a valine rather than a glutamate, because a single adenine (A) in the RNA is replaced by a uracil (U) at that point (a GAG or GAA replaced by a GUG or GUA).  So a fix might be relatively easy.  The tricky part for any tribunal is that the very warping of the red blood cells that causes all the nasty side effects makes it hard for the malaria parasite to live in them.  Similar issues complicate the various defects that lead to cystic fibrosis, with the ability to resist the effects (even in heterozygotes to a degree) of the toxin released by the phage in Vibrio cholerae, which messes with the chloride ion pumps and causes massive dehydration.


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